Compounds and methods of use

ABSTRACT

The present invention provides compounds useful in treating or preventing inflammation acne, bacterial conditions and promoting the appearance of healthy skin and compositions including these compounds.

REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Application Ser. No.62/446,358, filed Jan. 13, 2017, and U.S. Application Ser. No.62/490,592, filed Apr. 26, 2017, each of these applications being herebyincorporated herein by reference in their entirety as if it were part ofthe present disclosure.

BACKGROUND

There remains a need for novel treatment of inflammation, including, butnot limited to, inflammation associated with skin diseases and disorders(e.g., rosacea, atopic dermatitis, seborrheic dermatitis, psoriasis).There also remains a need to kill, inactivate, decolonize and/or inhibitthe growth of bacteria in a subject. There also remains a need for noveltreatment of acne and for the general promotion of healthy looking skin.

SUMMARY

The present invention also provides compositions containing compoundsdescribed herein, methods of preparing such compounds and/orcompositions, and methods of using such compounds and/or compositions.

In some embodiments, the present invention provides compositions fortreating or preventing inflammation comprising at least one presentlydisclosed compound, a carrier and optionally an additional activeingredient.

In some embodiments, topical compositions for treating or preventing askin disease or condition are provided, comprising at least one compoundof the present invention, a carrier and optionally an additional activeingredient, formulated for topical administration. In certainembodiments, provided herein are topical compositions for promotinghealthy skin in a subject comprising at least one presently disclosedcompound, a carrier and, optionally, an additional active ingredient.

In some embodiments, the present invention provides uses of providedcompounds and/or compositions in the treatment of inflammation, such asskin inflammation. In certain embodiments, the present inventionprovides uses of provided compounds and/or compositions in the treatmentof diseases that may benefit from inhibition of infiltration andactivation of inflammatory cells (e.g. neutrophils, lymphocytes,monocytes, mast cells), and/or inhibition of expression and activationof cell surface adhesion molecules (e.g. VCAM-1 and ICAM-1) inendothelial and inflammatory cells. In some embodiments, such includestreating or lessening the severity of inflammatory diseases or disordersselected from inflammation (acute or chronic), inflammation associatedwith spinal cord injury to promote nerve regeneration, inhibition ofrejection of genetically engineered cells by the immune system during invivo gene therapy, asthma, autoimmune diseases, and chronic obstructivepulmonary disease (COPD) (e.g., emphysema, chronic bronchitis and smallairways disease, etc.), inflammatory responses of the immune system,skin diseases (e.g., reducing acute skin irritation for patientssuffering from rosacea, atopic dermatitis, seborrheic dermatitis,psoriasis), irritable bowel syndrome (e.g., Crohn's disease andulcerative colitis, etc.), neurodegenerative disorders (e.g.,Parkinson's disease, Alzheimer's disease, Huntington's disease, Dementiapugilistica, Pick's disease, Guam parkinsonism dementia complex,Fronto-temporal dementia, Cortico-basal degeneration,Pallido-pontal-nigral degeneration, Progressive supranuclear palsy,Dementia with Lewy bodies (DLB), and multiple system atrophy (MSA)).

In some embodiments, the present invention provides methods for treatingor preventing diseases in a subject that may benefit from the modulationof levels of inflammatory mediators such as cytokines comprisingadministering the presently disclosed compounds and/or compositionscontaining one or more of the presently disclosed compounds. In certainembodiments, the present invention provides methods for treating orpreventing diseases in a subject that may benefit from the inhibition ofinfiltration and accumulation of helper-T lymphocytes comprisingadministering the presently disclosed compounds and/or compositionscontaining one or more of the presently disclosed compounds. In certainembodiments, the present invention provides methods for treating orpreventing diseases in a subject that may benefit from the inhibition ofICMT comprising administering the presently disclosed compounds and/orcompositions containing one or more of the presently disclosedcompounds. In certain embodiments, the present invention providesmethods for treating or preventing diseases in a subject that maybenefit from inhibition of oxidative burst response from neutrophilscomprising administering the presently disclosed compounds and/orcompositions containing one or more of the presently disclosedcompounds.

In some embodiments, provided herein are methods for treating orpreventing skin conditions (e.g., acne or atopic dermatitis), saidmethods comprising the step of topically applying onto a surface of asubject, including a human, in need thereof, an effective amount of atleast one presently disclosed compound of the present invention. Incertain embodiments, provided herein are methods of promoting healthyskin, said methods comprising the step of topically applying onto asurface of a subject, including a human, in need thereof, an effectiveamount of at least one presently disclosed compound.

In certain embodiments, the present invention provides methods fortreating or preventing inflammation in a subject, methods comprising thestep of administering an effective amount of at least one presentlydisclosed compound.

The present invention, provides, inter alia, methods to kill,inactivate, decolonize and/or inhibit the growth of bacteria on asurface. In some embodiments, the present invention provides methods totreat, prevent or ameliorate the symptoms of epithelial-relatedconditions, caused or aggravated by bacteria in a subject in needthereof.

In some embodiments, the present invention provides methods to treat,prevent and/or ameliorate symptoms of inflammation associated withepithelial-related conditions caused or aggravated by bacteria saidmethods comprising the step of administering to a subject (e.g.,topically applying onto a surface of a subject, including a human) inneed thereof, an effective amount of at least one presently disclosedcompound of the present invention. In some embodiments,epithelial-related conditions caused or aggravated by bacteria includeskin conditions, or respiratory conditions, or nasal conditions, orocular conditions, or oral conditions. In some embodiments,epithelial-related conditions caused or aggravated by bacteria includeconditions of the external ear. In some embodiments, epithelial-relatedconditions caused or aggravated by bacteria include vaginal conditions.In some embodiments, epithelial-related conditions caused or aggravatedby bacteria include genitourinary conditions, or rectal conditions.

DETAILED DESCRIPTION Definitions

“Anti-bacterial agent”: As used herein, the term “anti-bacterial agent”refers to an agent that inhibits the growth of a bacterium or kills abacterium or results in bacterial decolonization of a surface. In someembodiments, the anti-bacterial agent can have bactericidal effect. Insome embodiments, the anti-bacterial agent can have bacteristaticeffect. In some embodiments, the anti-bacterial agent can have bothbactericidal and bacteristatic effects. As used herein, the term“anti-bacterial agent” refers to both an antibacterial compound orpharmaceutically acceptable salts thereof.

“Acyl”: As used herein, the term “acyl” refers to a radical formed froman organic acid by removal of a hydroxyl group.

“Additional active ingredient”: As used herein, the phrase “additionalactive ingredient” refers to an agent, other than a presently disclosedcompound that exerts a pharmacological, dermatological or any otherbeneficial activity. It is to be understood that “other beneficialactivity” may be one that is only perceived as such by the subject usingthe inventive compositions. Typically, an additional active ingredient,as that term is used herein, refers to a pharmaceutically active agentthat is administered in combination with a compound of the presentinvention.

“Aliphatic”: The term “aliphatic”, as used herein, includes bothsaturated and unsaturated, straight chain (i.e., unbranched), branched,acyclic, cyclic, or polycyclic aliphatic hydrocarbons, which areoptionally substituted with one or more functional groups. As will beappreciated by one of ordinary skill in the art, “aliphatic” is intendedherein to include, but is not limited to, alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, cycloalkynyl moieties. Thus, as used herein,the term “alkyl” includes straight, branched and cyclic alkyl groups(see below). An analogous convention applies to other generic terms suchas “alkenyl”, “alkynyl”, and the like. Furthermore, as used herein, theterms “alkyl”, “alkenyl”, “alkynyl”, and the like encompass bothsubstituted and unsubstituted groups. In some embodiments, an aliphaticgroup contains 1-25 aliphatic carbon atoms. In some embodiments, analiphatic group contains from 1 to 25, from 1 to 24, from 1 to 23, from1 to 22, from 1 to 21, from 1 to 20, from 1 to 19, from 1 to 18, from 1to 17, from 1 to 16, from 1 to 15, from 1 to 14, from 1 to 13, from 1 to12, from 1 to 11, from 1 to 10, from 1 to 9, from 1 to 8, from 1 to 7,from 1 to 6, from 1 to 5, from 1 to 4, from 1 to 3, from 1 to 2, from 2to 3, or 3 to 4, 4 to 5, 5 to 6, 6 to 7, 7 to 8, 8 to 9, 9 to 10, 10 to11, 11 to 12, 12 to 13, 13 to 14, 14 to 15, 15 to 16, 16 to 17, 17 to18, 18 to 19, 19 to 20, 20 to 21, 21 to 22, 22 to 23, 23 to 24, or 24 to25 aliphatic carbon atoms. In certain embodiments, as used herein,“lower alkyl” is used to indicate those alkyl groups (cyclic, acyclic,substituted, unsubstituted, branched, or unbranched) having 1-6 carbonatoms. In some embodiments, wherein a portion of a term such as alkyl,alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl is used withina different generic term (e.g., dialkylamino, alkoxy, alkylthio,alkylamino), then it is understood that an analogous convention applieswith respect to the number of carbon atoms present.

“Alkenyl”: As used herein, the term “alkenyl” denotes a substituted orunsubstituted, monovalent group derived from a straight- orbranched-chain hydrocarbon moiety containing at least one carbon-carbondouble bond by removal of a single hydrogen atom. In some embodiments,the alkenyl group contains 1-25 aliphatic carbon atoms. In certainembodiments, an alkenyl group employed in the invention contains 10-25carbon atoms. In certain embodiments, an alkenyl group employed in theinvention contains 10-20 carbon atoms. In certain embodiments, analkenyl group employed in the invention contains 10-15 carbon atoms. Incertain embodiments, an alkenyl group employed contains 10 carbon atoms.In certain embodiments, an alkenyl group employed contains 15 carbonatoms. In certain embodiments, an alkenyl group employed contains 20carbon atoms. Alkenyl groups include, for example, decenyl, undecenyl,dodecenyl, tridecenyl, tetradecenyl, pentadecenyl, hexadecenyl,heptadecenyl, octadecenyl, nonadecenyl, eicosenyl, heneicosenyl,docosenyl, tricosenyl, tetracosenyl, pentacosenyl, polyunsaturatedalkenes including octadec-9,12-dienyl, octadec-9,12,15-trienyl,eicos-5,8,11,14-tetraenyl, farnesyl, geranyl, and geranylgeranyl, C-20phytyl, and the like.

“Alkenylene”: The term “alkenylene” refers to a bivalent, substituted orunsubstituted, alkenyl group. A substituted alkenylene chain is apolymethylene group containing at least one double bond in which one ormore hydrogen atoms are replaced with a substituent. Suitablesubstituents include those described herein for a substituted aliphaticgroup.

“Alkyl”: As used herein, the term “alkyl” means substituted orunsubstituted, saturated, straight- or branched-chain hydrocarbonradicals derived from an aliphatic moiety by removal of a singlehydrogen atom. In some embodiments, the alkyl group contains 1-25aliphatic carbon atoms. In certain embodiments, an alkyl group employedin the invention contains 10-25 carbon atoms. In certain embodiments, analkyl group employed in the invention contains 10-20 carbon atoms. Incertain embodiments, an alkyl group employed in the invention contains15-20 carbon atoms. In certain embodiments, an alkyl group employedcontains 10 carbon atoms. In certain embodiments, an alkyl groupemployed contains 15 carbon atoms. In certain embodiments, an alkylgroup employed contains 20 carbon atoms. In certain embodiments, analkyl group employed in the invention contains 1-3 carbon atoms. Incertain embodiments, an alkyl group employed contains 1-2 carbon atoms.In certain embodiments, an alkyl group contains 1 carbon atom. Examplesof alkyl radicals include, but are not limited to, methyl, ethyl,n-propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, sec-pentyl,iso-pentyl, tert-butyl, n-pentyl, neopentyl, n-hexyl, sec-hexyl,n-heptyl, n-octyl, n-decyl, n-undecyl, dodecyl, tridecyl, tetradecyl,pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl,heneicosyl, docosyl, tricosyl, teteracosyl, pentacosyl, and the like.

“Alkylamino”: The term “alkylamino” refers to a substituted orunsubstituted group having the structure —NHR′, wherein R′ is aliphatic,as defined herein. In certain embodiments, the aliphatic group contains1-20 aliphatic carbon atoms. In some embodiments, the aliphatic groupcontains 1-10 aliphatic carbon atoms. In some embodiments, the aliphaticgroup employed in the invention contains 1-8 aliphatic carbon atoms. Instill other embodiments, the aliphatic group contains 1-6 aliphaticcarbon atoms. In yet other embodiments, the aliphatic group contains 1-4aliphatic carbon atoms. Examples of alkylamino groups include, but arenot limited to, methylamino, ethylamino, n-propylamino, iso-propylamino,cyclopropylamino, n-butylamino, tert-butylamino, neopentylamino,n-pentylamino, hexylamino, cyclohexylamino, and the like.

“Alkylene”: The term “alkylene” refers to a bivalent substituted orunsubstituted alkyl group. Unless otherwise specified, the alkylenegroup contains 1-25 aliphatic carbon atoms. An “alkylene chain” is apolymethylene group, i.e., —(CH₂)_(n)—, wherein n is a positive integer,preferably from 1 to 6, from 1 to 5, from 1 to 4, from 1 to 3, from 1 to2, from 2 to 3, from 3 to 4, from 4 to 5, or from 5 to 6. A substitutedalkylene chain is a polymethylene group in which one or more methylenehydrogen atoms are replaced with a substituent. Suitable substituentsinclude those described herein for a substituted aliphatic group.

“Alkynyl”: As used herein, the term “alkynyl” denotes a substituted orunsubstituted monovalent group derived from a straight- orbranched-chain hydrocarbon moiety containing at least one carbon-carbontriple bond by removal of a single hydrogen atom. In certainembodiments, an alkynyl group employed in the invention contains 10-25carbon atoms. In certain embodiments, an alkynyl group employed in theinvention contains 10-20 carbon atoms. In certain embodiments, analkynyl group employed contains 10 carbon atoms. In certain embodiments,an alkynyl group employed contains 15 carbon atoms. In certainembodiments, an alkynyl group employed contains 20 carbon atoms. Incertain embodiments, an alkynyl group employed in the invention contains2-3 carbon atoms. In certain embodiments, an alkynyl group employedcontains 2 carbon atoms. In certain embodiments, an alkynyl groupemployed contains 3 carbon atoms. Representative alkynyl groups include,but are not limited to, ethynyl, 2-propynyl (propargyl), 1-propynyl, andthe like.

“Alkoxy”, or “Alkylthio”: The term “alkoxy”, or “alkylthio” as usedherein refers to a substituted or unsubstituted alkyl group, aspreviously defined, attached to the parent molecule through an oxygenatom or through a sulfur atom. In certain embodiments, the “alk” or“alkyl” portion of an “alkoxy” or “alkylthio” group contains 1-10aliphatic carbon atoms. In yet other embodiments, the “alk” or “alkyl”portion of an “alkoxy” or “alkylthio” group employed in the presentinvention contains 1-8 aliphatic carbon atoms. In still otherembodiments, the “alk” or “alkyl” portion of an “alkoxy” or “alkylthio”group contains 1-6 aliphatic carbon atoms. In yet other embodiments, the“alk” or “alkyl” portion of an “alkoxy” or “alkylthio” group contains1-4 aliphatic carbon atoms. Examples of alkoxy, include but are notlimited to, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, tert-butoxy,neopentoxy, and n-hexoxy. Examples of thioalkyl groups include, but arenot limited to, methylthio, ethylthio, propylthio, isopropylthio,n-butylthio, and the like.

“Animal”: The term animal, as used herein, refers to humans as well asnon-human animals, including, for example, mammals, birds, reptiles,amphibians, and fish. Preferably, the non-human animal is a mammal(e.g., a rodent, a mouse, a rat, a rabbit, a monkey, a dog, a cat, aprimate, or a pig). A non-human animal may be a transgenic animal. Insome embodiments, the term animal is used to refer to veterinary animals(e.g., fowl, cows, pigs, horses, etc.).

“Aralkylene” refers to a divalent group of formula —R^(a)—Ar^(a)— whereR^(a) is an “alkylene” as defined herein, and Ar^(a) is an “arylene” asdefined herein (i.e., an alkylene is bonded to an arylene).

“Anti-dandruff agent”: As used herein, the term “anti-dandruff agent” isan agent that reduces, eliminates or prevents a scurf from forming onskin, especially of the scalp, that comes off in small white or grayishscales. Exemplary anti-dandruff ingredients usable in context of thepresent invention include, without limitation, butoconazole, climbazole,coal tar, clotrimazole, dichlorophenyl imidazolodioxalan, imidazoles(e.g., fluconazole, ketoconazole, itraconazole, miconazole,miconazolenitrite, povidone-iodine, sulconazole, tioconazole), salicylicacid, selenium sulfide, shale oil and the like (e.g., sulfonated shaleoil), sulfur, zinc pyrithione, and the like, and any possible stereoisomers thereof such as anthralin, piroctone olamine (Octopirox),selenium sulfide, and ciclopiroxolamine, and combinations thereof.

“Antihistamine agent”: As used herein, the term “antihistamine agent” isan agent that counteracts histamine in the body and that is used fortreating allergic reactions (such as hay fever) and cold symptoms.Non-limiting examples of antihistamines usable in context of the presentinvention include astemizole, brompheniramine, chlorpheniramine,clemastine, dexchlorpheniramine, diphenhydramine, loratadine,piperidines, piperazines, promethazine, terfenadine and tripolidine andcombinations thereof.

“Anti-irritant”: The term “anti-irritant”, as used herein, is an agentthat prevents or reduces soreness, roughness, or inflammation of abodily part (e.g., skin). Presently known anti-irritants can be dividedinto water-soluble anti-irritants and water-insoluble anti-irritants.Representative examples of such compositions are described, for example,in U.S. Pat. No. 5,482,710, which is herein incorporated by reference.Suitable anti-irritants that can be used in the context of the presentinvention include, for example, steroidal and non-steroidalanti-inflammatory agents or other materials such as allantoin, aloevera, alpha-bisabolol, caffeine, chamomile, cola nitida extract, greentea extract, glycyrrhizic acid, licorice extract, tea tree oil, or otherxanthines, and combinations thereof.

“Anti-oxidant agent”: As used herein, the term “anti-oxidant agent” isan agent that inhibits oxidation or reactions promoted by oxygen orperoxides. Non-limiting examples of anti-oxidants that are usable in thecontext of the present invention include amines (e.g.,N,N-diethylhydroxylamine, amino-guanidine), arginine pilolate, ascorbicacid (vitamin C) and its salts, ascorbyl esters of fatty acids, ascorbicacid and the like (e.g., magnesium ascorbyl phosphate, sodium ascorbylphosphate, ascorbyl sorbate), bioflavonoids, butylated hydroxy benzoicacids and their salts, curcumin, dihydroxy fumaric acid and its salts,gallic acid and its alkyl esters (e.g., propyl gallate, uric acid andits salts and alkyl esters), glycine pidolate, grape skin/seed extracts,6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (commerciallyavailable under the tradename Trolox®), lipoic acid, lysine, melanin,methionine, nordihydroguaiaretic acid, proline, rosemary extracts,silymarin, sorbic acid and its salts, sulfhydryl compounds (e.g.,glutathione), superoxide dismutase, tea extracts, tocopherol acetate,tocopherol (vitamin E), tocopherol sorbate, and other esters oftocopherol and combinations thereof. In certain non-limitingembodiments, the antioxidant can be selected from one or more ofbutylated hydroxyanisole, butylated hydroxytoluene, sodium metabisulfiteand tert-butylhydroquinone.

“Antipruritic agents”: As used herein, the term “antipruritic agent” asused herein, is an agent that reduces, eliminates or prevents itching.Suitable antipruritic agents include, without limitation, methdilazineand trimeprazine, and combinations thereof.

“Anti-skin atrophy actives”: As used herein, the term “anti-skin atrophyactive” is an agent that is effective in replenishing or rejuvenatingthe epidermal layer by promoting or maintaining the natural process ofdesquamation. Examples of antiwrinkle and antiskin atrophy actives whichcan be used in context of the present invention include alpha-hydroxyacids (e.g. glycolic acid, and lactic acid), lipoic acid,lysophosphatidic acid, phytic acid, retinoic acid, its prodrugs, isomers(e.g., cis and trans) and analogues thereof, salicylic acid and thelike, sclerosing agents or sclerosants, skin peel agents (e.g., phenoland the like), sulfur-containing D and L amino acids and the like andrelated salts, (e.g., N-acetyl derivatives, such as N-acetylL-cysteine), and thiols (e.g. ethane thiol).

“Anesthetic agents”: The term “anesthetic agent” as used herein is anagent that results in a reduction or loss of sensation. Non-limitingexamples of anesthetic drugs that are suitable for use in the context ofthe present invention include pharmaceutically acceptable salts ofbupivacaine, chloroprocaine, cocaine, dibucaine, dyclonine, etidocaine,hexylcaine, ketamine, lidocaine, mepivacaine, phenol, pramoxine,procaine, and tetracaine.

“Aryl” and “Heteroaryl”: In general, the terms “aryl” and “heteroaryl”refer to substituted or unsubstituted aromatic groups or moieties. Insome embodiments, the terms “aryl” and “heteroaryl” may be used in thecontext of a different moiety name (e.g., “arylalkyl”, “aralkylene”,“aryloxy”, “heteroaryloxy” or “heteroarylalkyl”). In some embodiments,an “aryl” and/or “heteroaryl” refer to stable mono- or polycyclic,heterocyclic, polycyclic, and polyheterocyclic unsaturated moietieswherein at least one ring in the system is aromatic. In someembodiments, an “aryl” and/or “heteroaryl” ring system contains three toseven ring members. In some embodiments, an “aryl” and/or “heteroaryl”contain 3-14 carbon atoms. In certain embodiments of the presentinvention, “aryl” refers to a mono- or bicyclic carbocyclic ring systemhaving one or two aromatic rings including, but not limited to, phenyl,naphthyl, tetrahydronaphthyl, indanyl, indenyl, and the like. In certainembodiments of the present invention, the term “heteroaryl”, as usedherein, refers to a cyclic aromatic radical having from five to ten ringatoms of which one ring atom is selected from S, O, and N; zero, one, ortwo ring atoms are additional heteroatoms independently selected from S,O, and N; and the remaining ring atoms are carbon, the radical beingjoined to the rest of the molecule via any of the ring atoms, such as,for example, pyridyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl,imidazolyl, thiazolyl, oxazolyl, isooxazolyl, thiadiazolyl, oxadiazolyl,thiophenyl, furanyl, quinolinyl, isoquinolinyl, and the like. It will beappreciated that aryl and heteroaryl groups can be unsubstituted orsubstituted, wherein substitution includes replacement of one, two,three, or more of the hydrogen atoms thereon independently with any oneor more of the moieties (e.g., “substituents”) provided herein.

“Arylene” and “Heteroarylene”: The term “arylene” refers to anunsubstituted or substituted divalent group that is carbocyclic andaromatic. In some embodiments, rings in an arylene group are fused toone another. In some embodiments rings in an arylene group are notfused, but are nonetheless connected. In some embodiments, an arylenegroup includes some fused rings and some connected rings. In someembodiments, an arylene group includes aromatic rings. In someembodiments, an arylene group includes non-aromatic rings. In someembodiments, an arylene group includes some aromatic rings and somenon-aromatic rings. In some embodiments, the arylene group has up to 5rings, up to 4 rings, up to 3 rings, up to 2 rings, or one aromaticring. For example, the arylene group can be phenylene. Exemplary arylenegroups include any of the “aryl” moieties listed herein with theunderstanding that divalency is required to arrive at a corresponding“arylene” group from an “aryl” group. Exemplary substituents of“arylene” groups include replacement of one, two, three, or more of thehydrogen atoms thereon independently with any one or more of themoieties applicable for “aryl” and “heteroaryl,” as defined herein. Itwill be appreciated by one skilled in the art that a carbon ring atom ofan “arylene” can be replaced by one, two or three heteroatomsindependently selected from S, O, and N while the remaining ring atomsare carbon, the divalent group being joined to the rest of the moleculevia any two ring atoms, to form a “heteroarylene”. Exemplary“heteroarylene” groups include any of the “heteroaryl” moieties listedherein with the understanding that divalency is required to arrive at acorresponding “heteroarylene” group from a “heteroaryl” group.

“Associated with”: When two entities are “associated with” one anotheras described herein, they are linked by a direct or indirect covalent ornon-covalent interaction. Preferably, the association is covalent.Desirable non-covalent interactions include hydrogen bonding, van derWaals interactions, hydrophobic interactions, magnetic interactions,electrostatic interactions, etc.

“Astringent”: As used herein, the term “astringent” is an agent thatdraws together or constricts body tissues and is effective in stoppingthe flow of blood or other secretions. In some embodiments, anastringent coagulate blood, and therefore can be used to arresthemorrhage. In some embodiments, an astringent promotes healing,toughens skin and/or to decreases sweating. In some embodimentsastringents are protein precipitants. Typically, astringents have lowcell penetrability such that their action is limited to the cell surfaceand/or interstitial spaces. In some embodiments, astringent action isaccompanied by contraction and wrinkling of tissues to which astringentsare applied. In some embodiments, application of astringents isaccompanied by blanching of recipient tissue. In some embodiments,astringents include one or more agents such as aluminum, bismuth, iron,manganese, zinc. Alternatively, and/or additionally, such agents can beprovided in any of a variety of forms including, for example,pharmaceutically acceptable salt forms.

“Carrier”: The term “carrier” is used in accordance with itsart-understood meaning, to refer to a material that is included in apharmaceutical composition but does not abrogate the biological activityof pharmaceutically active agent(s) that are also included within thecomposition. Pharmaceutical carriers are typically of sufficiently highpurity and sufficiently low toxicity to render it suitable foradministration to the subject being treated. In some embodiments,carriers are inert. In some embodiments, carriers are affirmativelybeneficial (e.g., providing pharmaceutical and/or cosmetic benefits). Insome embodiments, AFC acts as an acceptable carrier. In someembodiments, the term “carrier” when used in the pharmaceutical context(e.g., pharmaceutically acceptable carrier) means that an agent ispresent in a composition but does not abrogate the biological activityof another agent(s) present in a composition. In some embodiments, theterm “carrier” when used in a cosmetic context (e.g., cosmeticallyacceptable carrier) means that an agent is present in a composition butdoes not but does not abrogate the biological activity and/or aestheticeffect of another agent(s) present in a composition. In someembodiments, a cosmetically acceptable carrier is used to topicallyadminister cosmetics with which presently disclosed compounds of thepresent invention will remain stable and bioavailable. It will beunderstood that “cosmetically acceptable carriers” and “carriers” asdefined herein are similar, if not often identical, in nature. In someembodiments, the term “carrier” when used in a cosmeceutical context(e.g., cosmeceutical carrier) means that an agent is present in acomposition but does not abrogate the biological activity and aestheticeffect of another agent(s) present in a composition. Pharmaceuticalcarriers further, in certain embodiments, maintain the stability andbioavailability of an active agent (i.e. a presently disclosed compoundof the present invention). Pharmaceutical carriers can be liquid orsolid and are selected with the planned manner of administration inmind, to provide for the desired bulk, consistency, etc., when combinedwith an active agent and other components of a given composition.

“Caustic agents”: As used herein, the term “caustic agent” is an agentthat is capable of destroying or eating away epithelial tissue bychemical action. Caustic agents can be used to remove dead skin cells.For example, beta-hydroxy acids, naturally derived acids with a strongkerolytic effect, are useful for problem skin or peeling.

“Chelating Agent”: The term “chelating agent” as used herein, is anagent that binds to a metal ion such as calcium (Ca²⁺), magnesium (Mg²⁺)and copper (Cu²⁺), forming a metal complex known as a chelate. In someembodiments, a chelating agent is a ligand. In some embodiments, achelating agent is an atom. In some embodiments, a chelating agent is anion. In some embodiments, a pharmaceutical composition may contain achelating agent (e.g., a mild agent, such as, ethylenediaminetetraaceticacid (“EDTA”), EDTA derivatives, or combinations thereof). In someembodiments, a chelating agent enhances a preservative or preservativesystem of the composition.

“Colorants”: As used herein, the term “colorant” refers to pigmentsand/or dyes or a combination thereof, that are used to change hair coloras cosmetic benefit requires. In some embodiments, pigments included in“colorants” include, but are not limited to, iron oxides, and titaniumoxides. In some embodiments, dyes included in “colorants” include D&Capproved colorants, FD&C approved colorants, and those approved for usein Europe and Japan. See Marmion, D. M., Handbook of US Colorants forFood, Drugs, Cosmetics, and Medical Devices, 3rd ed, 1991 hereinincorporated by reference.

“Compatible”: The term “compatible” as used herein means that thecomponents of such a composition are capable of being combined with eachother in a manner such that there is no interaction that wouldsubstantially reduce the efficacy of the composition under ordinary useconditions.

“Demulcent”: As used herein, the term “demulcent” is an agent used toprimarily alleviate irritation, particularly mucous membranes or abradedtissues. Exemplary demulcents include acacia, agar, alginates,mucilages, benzoin, carbomer, gelatin, glycerin, gums, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose,hydrogels, dextrins, starches, certain sugars, and polymeric polyhydricglycols, propylene glycol, sodium alginate, tragacanth, and combinationsthereof.

“Deodorant agent”: As used herein, the term “deodorant agent” refers toa substance for inhibiting or masking perspiration or other bodilyodors. Representative examples of deodorant agents that are usable inthe context of the present invention include, without limitation,quaternary ammonium compounds such as benzethonium chloride, cetylpyridinium chloride, cetyl-trimethylammonium bromide, diisobutyl phenoxyethoxy ethyl dimethyl benzyl ammonium chloride, lauroyl sarcosine,sodium aluminum chlorohydroxy lactate, sodium N-lauryl sarcosine, sodiumN-palmityl sarcosine, N-myristoyl glycine, potassium N-lauryl sarcosine,stearyl, trimethyl ammonium chloride, tricetylmethyl ammonium chloride,2,4,4′-trichloro-2′-hydroxy diphenyl ether, diaminoalkyl amides such asL-lysine hexadecyl amide, heavy metal salts of citrate, salicylate, andpiroctose, especially zinc salts, and acids thereof, heavy metal saltsof pyrithione, especially zinc pyrithione and zinc phenolsulfate. Otherdeodorant agents include, without limitation, odor absorbing materialssuch as carbonate and bicarbonate salts (e.g. as the alkali metalcarbonates and bicarbonates, ammonium and tetraalkylammonium carbonatesand bicarbonates, especially the sodium and potassium salts) orcombination thereof.

“Dialkylamino”: The term “dialkylamino” refers to a group having thestructure —NRR′, wherein R and R′ are each an aliphatic group, asdefined herein. R and R′ may be the same or different in a dialkyaminomoiety. In certain embodiments, the aliphatic group contains 1-20aliphatic carbon atoms. In some embodiments, the aliphatic groupcontains 1-10 aliphatic carbon atoms. In yet other embodiments, thealiphatic groups employed in the invention contain 1-8 aliphatic carbonatoms. In still other embodiments, the aliphatic group contains 1-6aliphatic carbon atoms. In yet other embodiments, the aliphatic groupcontains 1-4 aliphatic carbon atoms. Examples of dialkylamino groupsinclude, but are not limited to, dimethylamino, methyl ethylamino,diethylamino, methylpropylamino, di (n-propyl) amino,di(iso-propyl)amino, di(cyclopropyl)amino, di(n-butyl)amino,di(tert-butyl)amino, di(neopentyl)amino, di(n-pentyl)amino,di(hexyl)amino, di(cyclohexyl)amino, and the like. In certainembodiments, R and R′ are linked to form a cyclic structure. Theresulting cyclic structure may be aromatic or non-aromatic. Examples ofcyclic diaminoalkyl groups include, but are not limited to, aziridinyl,pyrrolidinyl, piperidinyl, morpholinyl, pyrrolyl, imidazolyl,1,3,4-trianolyl, and tetrazolyl.

“Effective amount”: In general, the “effective amount” of an activeagent (e.g., a therapeutic agent, composition, and/or formulation)refers to an amount sufficient to elicit the desired biologicalresponse. In some embodiments, a therapeutically effective amount of asubstance is an amount that is sufficient, when administered to asubject suffering from or susceptible to a disease, disorder, and/orcondition, to treat, diagnose, prevent, and/or delay the onset of one ormore symptoms of the disease, disorder, and/or condition. As will beappreciated by those of ordinary skill in this art, and effective amountof a substance may vary depending on such factors as the desiredbiological endpoint, the substance to be delivered, the pharmacokineticsof the compound, the target cell or tissue, the disease being treated,the mode of administration, and the patient, etc. For example, theeffective amount of a composition and/or formulation to treat a disease,disorder, and/or condition is the amount that alleviates, ameliorates,relieves, inhibits, prevents, delays onset of, reduces severity ofand/or reduces incidence of one or more symptoms or features of thedisease, disorder, and/or condition. Those of ordinary skill in the artwill appreciate that, commonly, a therapeutically effective amount willbe administered over a series of individual doses. In some embodiments,the term “effective amount” when used in a pharmaceutical context (e.g.,pharmaceutically effective amount) means that an agent is present in anamount sufficient to achieve a desired therapeutic effect. In someembodiments, the term “effective amount” when used in a cosmetic context(e.g., cosmetically effective amount) means that an agent is present inan amount sufficient to achieve an aesthetic effect. In someembodiments, the term “effective amount” when used in a cosmeceuticalcontext (e.g., cosmeceutically effective amount) means that an agent ispresent in an amount sufficient to achieve a therapeutic and/oraesthetic effect.

“Emollients”: As used herein, the term “emollients” refers to an agentthat increases tissue moisture content, thereby rendering skin softerand more pliable. Increased moisture content in the skin can be achievedby preventing water loss with an occlusive water-immiscible barrier, byincreasing the water-holding capacity in the skin with humectants, or byaltering the desquamation of the outermost skin layer, the stratumcorneum. In some embodiments, “emollients” are typically bland, fatty oroleaginous materials which can be applied locally, particularly to theskin. Useful emollients include cetyl alcohol, glycerin, hydrophilicpetrolatum, isopropyl myristate, lanolin, mineral oil, myristyl alcohol,oleyl alcohol, paraffin, petrolatum, spermaceti, vegetable oils, waxes,white ointment, white petroleum, yellow ointment or combinationsthereof.

“Emulsifier”: The term “emulsifier” as used herein promotes formationand stabilization of an emulsion. Suitable emulsifiers may be finelydivided solids, natural materials, or synthetic materials. Naturalemulsifying agents may be derived from either animal or vegetablesources. Those from animal sources include casein, cholesterol, eggyolk, gelatin, or wool fat or combinations thereof. Those from vegetablesources include acacia, chondrus, pectin or tragacanth or combinationsthereof. Vegetable sources specifically from cellulose derivativesinclude carboxymethyl cellulose and methyl cellulose to increase theviscosity. Finely divided emulsifiers include aluminum hydroxide,bentonite, magnesium hydroxide, or magnesium trisylicate. Syntheticagents include anionic, cationic or nonionic agents, and includebenzalkonium chloride, polyethylene glycol 400 monostearate, sodiumlauryl sulfate, or combinations thereof.

“Enantiomerically enriched” and “Enantioenriched”: As used herein, theterms “enantiomerically enriched” and “enantioenriched” denote that oneenantiomer is enriched with respect to other enantiomers of the samecompound in a composition. For example, when a compound is substantiallyin the R-form or the S-form with respect to a particular chiral center,the compound may be considered to have an enantiomeric excess (ee) forthat form. In some embodiments, a composition is considered “enriched”when one enantiomer is present in at least 75% ee in the composition. Incertain embodiments, the terms denote that one enantiomer is present inat least 80% ee, 85% ee, 90% ee, 95% ee, 97.5% ee, or more. In someembodiments, a composition is considered “enantiomerically pure” or“enantiopure” when one enantiomer is present with an ee of at leastabout 90%, with respect to other enantiomers. In some embodiments, acomposition is considered “enantiomerically pure” or “enantiopure” whenone enantiomer is present with an ee of at least about 95%, with respectto other enantiomer(s) present in the composition. In some embodiments,a composition is considered “enantiomerically pure” or “enantiopure”when one enantiomer is present with an ee of at least about 97.5%, withrespect to other enantiomer(s) present in the composition. In someembodiments, a composition is considered “enantiomerically pure” or“enantiopure” when one enantiomer is present with an ee of at leastabout 99%, with respect to other enantiomer(s) present in thecomposition.

“Fragrance”: As used herein, the term “fragrance” refers to an agenthaving a pleasant aroma. Suitable fragrances include, but are notlimited to, camphor synthetic, chamomile, clove oil, eucalyptus oil,lavender, peppermint oil, and the like.

“G-protein mediated condition”: The term “G-protein mediated condition”,as used herein means any disease or other deleterious condition forwhich the appearance, incidence, and/or severity of one or more symptomscorrelates with changes in a G-protein signaling cascade. In someembodiments, one or more symptoms of the disease or condition is causedby a defect or alteration in G-protein signaling.

“Hair Conditioning Agents”: As used herein, the term “hair conditioningagent” refers to an agent that is suitable for use in conditioning hair(e.g., so as to further improve the condition of the hair). In someembodiments, representative hair conditioning agents include, forexample, one or more alkoxylated alcohols, alkoxylated amides,alkoxylated carboxylic acids, cationic surfactants, collagens,dimethicone polyols, esters (e.g., glyceryl esters), halogenatedquaternary ammonium compounds, keratins, modified silicones, proteins,polymeric ethers, quaternary ammonium compounds, or sorbitanderivatives, or combinations thereof.

“Halo” and “Halogen”: The terms “halo” and “halogen” as used hereinrefer to an atom selected from fluorine, chlorine, bromine, and iodine.

“Heteroaliphatic”: The term “heteroaliphatic”, as used herein, refers toaliphatic moieties that contain one or more oxygen, sulfur, nitrogen,phosphorus, or silicon atoms, e.g., in place of carbon atoms.Heteroaliphatic moieties may be branched, unbranched, cyclic or acyclicand include saturated and unsaturated heterocycles such as morpholino,pyrrolidinyl, etc. In certain embodiments, heteroaliphatic moieties aresubstituted by independent replacement of one or more of the hydrogenatoms thereon with one or more moieties (e.g., “substituents”) describedherein.

“Heteroatom”: As used herein, the term “heteroatom” means one or more ofoxygen, sulfur, nitrogen, phosphorus, or silicon (including, anyoxidized form of nitrogen, sulfur, phosphorus, or silicon; thequaternized form of any basic nitrogen or; a substitutable nitrogen of aheterocyclic ring, for example N (as in 3,4-dihydro-2H-pyrrolyl), NH (asin pyrrolidinyl) or NR_(x) (as in N-substituted pyrrolidinyl)).

“Heterocycle” or “Heterocyclyl”: As used herein, the terms“heterocycle”, “heterocyclyl”, “heterocyclic radical”, and “heterocyclicring” are used interchangeably and refer to a stable 3- to 7-memberedmonocyclic or 7-10-membered bicyclic heterocyclic moiety that is eithersaturated or partially unsaturated, and having, in addition to carbonatoms, one or more, preferably one to four heteroatoms independentlyselected from nitrogen, oxygen, or sulfur. When used in reference to aring atom of a heterocycle, the term “nitrogen” includes a substitutednitrogen. As an example, in a saturated or partially unsaturated ringhaving 1-3 heteroatoms selected from oxygen, sulfur or nitrogen, thenitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as inpyrrolidinyl), or NR_(x) (as in N-substituted pyrrolidinyl).

A heterocyclic ring can be attached to its pendant group at anyheteroatom or carbon atom that results in a stable structure and any ofthe ring atoms can be optionally substituted. Examples of such saturatedor partially unsaturated heterocyclic radicals include, withoutlimitation, tetrahydrofuranyl, tetrahydrothiophenyl pyrrolidinyl,piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl,decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl,diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl. Theterms “heterocycle”, “heterocyclyl”, “heterocyclyl ring”, “heterocyclicgroup”, “heterocyclic moiety”, and “heterocyclic radical”, are usedinterchangeably herein, and also include groups in which a heterocyclylring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings,such as indolinyl, 3H-indolyl, chromanyl, phenanthridinyl, ortetrahydroquinolinyl, where the radical or point of attachment is on theheterocyclyl ring. In certain embodiments, one or more carbon atoms maybe substituted with an oxo group in the heterocyclyl ring. Examples ofsuch groups include, without limitation, an isoindolin-1,3-dione moiety.A heterocyclyl group may be mono- or bicyclic. The term“heterocyclylalkyl” refers to an alkyl group substituted by aheterocyclyl, wherein the alkyl and heterocyclyl portions independentlyare optionally substituted.

“Hormone”: As used herein, the term “hormone” refers to naturalsubstances produced by organs of the body that travel by blood totrigger activity in other locations or their synthetic analogs. Suitablehormones for use in the context of the present invention include, butare not limited to, calciferol (Vitamin D₃) and its products, androgens,estrogens and progesterones.

“Hydrocarbon”: The term “hydrocarbon”, as used herein, refers to anychemical group comprising hydrogen and carbon. In some embodiments, ahydrocarbon consists of hydrogen and carbon. A hydrocarbon may besubstituted or unsubstituted. A hydrocarbon may be unsaturated,saturated, branched, unbranched, cyclic, or polycyclic. Illustrativehydrocarbons include, for example, methyl, ethyl, n-propyl, iso-propyl,cyclopropyl, allyl, vinyl, n-butyl, tert-butyl, ethynyl, cyclohexyl,methoxy, diethylamino, and the like. As would be known to one skilled inthis art, all valencies must be satisfied in making any substitutions.As used herein, a “bivalent hydrocarbon” refers to alkylene, alkenylene,or alkynylene, etc.

“Hypopigmenting agents”: As used herein, the term “hypopigmentingagents” refers to substances capable of depigmenting the skin. Suitablehypopigmenting agents include hydroquinones, mequinol, and variousprotease inhibitors including serine protease inhibitors, active soy andretinoic acid.

“In combination”: As used herein, the phrase “in combination” refers toagents that are simultaneously administered to a subject. It will beappreciated that two or more agents are considered to be administered“in combination” whenever a subject is simultaneously exposed to both(or more) of the agents. Each of the two or more agents may beadministered according to a different schedule; it is not required thatindividual doses of different agents be administered at the same time,or in the same composition. Rather, so long as both (or more) agentsremain in the subject's body, they are considered to be administered “incombination”.

“Independently selected”: The term “independently selected” is usedherein to indicate that the referenced groups can be identical ordifferent.

“Irritant”: As used herein, the term “irritant” is a material that actslocally on the skin to induce, based on irritant concentration,hyperemia, inflammation, and desiccation. Irritant agents include, butare not limited to, alcohol, aromatic ammonia spirits, benzoin tincture,camphor capsicum, and coal tar extracts. In some embodiments, theirritant is a rubefacient.

“Modulate”: The term “modulate” refers to change in a parameter (e.g., achange in a binding interaction or an activity, etc.). Modulation canrefer to an increase or a decrease in the parameter (e.g., an increaseor decrease in binding, an increase or decrease in activity, etc.).

“Modulator”: The term “modulator” refers to an agent that alters leveland/or activity of its target in an inflammatory pathway. In someembodiments, a modulator alters interaction between a protein in aninflammatory pathway and one or more other entities. In someembodiments, a modulator alters interaction between a protein in aninflammatory pathway and a substrate. Determination of whether an agentis a modulator can be performed directly or indirectly. Determination ofwhether an agent modulates an interaction can be performed directly,e.g., using an assay that detects the interaction between a protein inan inflammatory pathway and a substrate. Determination of whether anagent modulates an interaction can be performed with a technique thatindirectly detects modulation, e.g., a technique that detects abiological activity that is downstream of, and dependent on, theprotein-substrate interaction. In certain embodiments, inflammatorypathways are G-protein-mediated (e.g., purinergic receptor-mediated). Incertain embodiments, inflammatory pathways are non-G-protein-mediated(e.g., PPAR-mediated, Toll-like receptor-mediated, and TNF-alphareceptor-mediated).

“Moisturizing agent”: As used herein a “moisturizing agent” is asubstance that adds or restores moisture to the skin. Representativeexamples of moisturizing or humectant agents that are usable in thepresent invention include, without limitation, acetamidemonoethanolamine urazole, aloe vera in any of its variety of forms(e.g., aloe vera gel), allantoin, guanidine, glycolic acid and glycolatesalts (e g ammonium salt and quaternary alkyl ammonium salt), hyaluronicacid, lactamide monoethanolamine, polyethylene glycols, polyhydroxyalcohols (e.g., sorbitol, glycerol, hexanetriol, propylene glycol,butylene glycol, hexylene glycol and the like), sugars and starches,sugar and starch derivatives (e.g., alkoxylated glucose), and anycombination thereof.

“Non-steroidal anti-inflammatory agents”: As used herein, the term“non-steroidal anti-inflammatory agents” refers to a large group ofagents that are aspirin-like in their action, including acetaminophen,Advil®, Aleve®, ibuprofen, naproxen sodium and Tylenol®. Additionalexamples of non-steroidal anti-inflammatory agents that are usable inthe context of the present invention include, without limitation, aceticacid derivatives (e.g., acematacin, clindanac, diclofenac, felbinac,fenclofenac, fentiazac, furofenac, indomethacin, isoxepac, ketorolac,oxepinac, sulindac, tiopinac, tolmetin, zidometacin and zomepirac),benorylate, diflunisal, disalcid, fenamates (e.g., flufenamic,meclofenamic, mefenamic, niflumic and tolfenamic acids), fendosal,oxicams (e.g., CP-14,304, isoxicam, piroxicam, sudoxicarn, andtenoxicam), propionic acid derivatives (e.g., alminoprofen,benoxaprofen, carprofen, fenbufen, fenoprofen, flurbiprofen, ibuprofen,indopropfen, ketoprofen, miroprofen, naproxen, oxaprozin, pirprofen,pranoprofen, suprofen, tiaprofenic and tioxaprofen), pyrazoles (e.g.,azapropazone, feprazone, oxyphenbutazone, phenylbutazone andtrimethazone), safapryn, solprin, trilisate.

“Partially Unsaturated”: As used herein, the term “partiallyunsaturated” refers to a ring moiety that includes at least one doubleor triple bond. The term “partially unsaturated” is intended toencompass rings having multiple sites of unsaturation, but is notintended to include aryl or heteroaryl moieties, as herein defined.

“Penetration enhancer” and “pharmaceutically acceptable penetrationenhancer”: The term “penetration enhancer” and “pharmaceuticallyacceptable penetration enhancer” as used herein is a non-toxic agentthat improves bioavailability of a topical composition. In someembodiments, a penetration enhancer is known to accelerate the deliveryof a substance through the skin (e.g., disrupting the barrier functionof the skin without compromising its barrier effects on microorganismsand toxins). Typically, a penetration enhancer is selected to benon-toxic to skin of the intended recipient (e.g., human). A penetrationenhancer is also desirably compatible with any pharmaceutically activeagent with which it is administered. Representative penetrationenhancers include, for example, and without limitation, such agents as1-substituted azacycloheptane-2-ones (e.g.,1-n-dodecylcyclazacycloheptan-2-one, available under the trademarkAzone® from Whitby Research Incorporated, Richmond, Va.),dipolar-aprotic solvents (e.g., N,N-dimethylacetamide (“DMA”),decylmethylsulfoxide (“C₁₀ MSO”), dimethyl formamide (“DMF”),dimethylsulfoxide (“DMSO”) and N-methyl-2-pyrrolidone (“NMP”)),phospholipids (e.g., allantoin, fatty acid alcohols, lecithin, alcoholsincluding glycerols such as polyethylene glycol monolaurate (“PGML”),glycerol monolaurate (“GML”), urazole, and the like). Penetrationenhancer also can be a vegetable oil, such as, but not limited to, cornoil, cottonseed oil, safflower oil, and olive oil. Additionalpenetration enhancers generally can be found in Remington: The Scienceand Practice of Pharmacy, 20^(th) ed. (Gennaro, A. R., et al., eds.)Lippincott Williams & Wilkins: Philadelphia (2000), which isincorporated herein by reference.

“pH adjusting agent”: As used herein, the term “pH adjusting agent” asused herein is an agent that imparts suitable pH characteristics tocompositions provided herein, (e.g., a substantially neutral pH), the pHof which depends on the specific utilization of the composition. In someembodiments, as the pH of skin is 5.5, it may be desirable to formulatecompositions for topical skin application (to avoid irritation) having apH value in a range of from about 4.0 to about 7.0, or in a range offrom about 5.0 and 6.0, or about 5.5, or substantially 5.5. Suitable pHadjusting agents include, for example, but are not limited to, one ormore adipic acids, buffers, citric acids, calcium hydroxides, glycines,magnesium aluminometasilicates, or combinations thereof.

“Pharmaceutically acceptable salt”: The term “pharmaceuticallyacceptable salt” refers to those salts which are, within the scope ofsound medical judgment, suitable for use in contact with the tissues ofhumans and lower animals without undue toxicity, irritation, allergicresponse, and the like, and are commensurate with a reasonablebenefit/risk ratio. Pharmaceutically acceptable salts are well known inthe art. For example, Berge et al. describe pharmaceutically acceptablesalts in detail in J. Pharmaceutical Sciences, 66: 1-19, 1977;incorporated herein by reference. Such salts can be prepared in situduring the final isolation and purification of the compounds of theinvention, or separately (e.g., by reacting the free base functionalitywith a suitable organic or inorganic acid). Alternatively, oradditionally, salts may form during formulation of a compound. Examplesof pharmaceutically acceptable, nontoxic acid addition salts are saltsof an amino group formed with inorganic acids such as hydrochloric acid,hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid orwith organic acids such as acetic acid, oxalic acid, maleic acid,tartaric acid, citric acid, succinic acid, or malonic acid or by usingother methods used in the art such as ion exchange. Otherpharmaceutically acceptable salts include adipate, alginate, ascorbate,aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate,camphorate, camphorsulfonate, citrate, cyclopentanepropionate,digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate,glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate,hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate,lactate, laurate, lauryl sulfate, malate, maleate, malonate,methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate,oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate,phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate,tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts,and the like. Representative alkali or alkaline earth metal saltsinclude sodium, disodium, lithium, potassium, calcium, magnesium, andthe like. Further pharmaceutically acceptable salts include, whenappropriate, nontoxic ammonium, quaternary ammonium, and amine cationsformed using counterions such as halide, hydroxide, carboxylate,sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.

“Pharmaceutically acceptable ester”: The term “pharmaceuticallyacceptable ester” refers to esters which hydrolyze in vivo and includethose that break down readily in the human body to leave the parentcompound or a salt thereof. Suitable ester groups include, for example,those derived from pharmaceutically acceptable aliphatic carboxylicacids, particularly alkanoic, alkenoic, cycloalkanoic, and alkanedioicacids, in which each alkyl or alkenyl moiety advantageously has not morethan 6 carbon atoms. Examples of particular esters include formates,acetates, propionates, butyrates, acrylates, and ethylsuccinates. Incertain embodiments, the esters are cleaved by enzymes such asesterases.

“Pharmaceutically acceptable prodrugs”: The term “pharmaceuticallyacceptable prodrugs” as used herein refers to those prodrugs of thecompounds of the present invention which are, within the scope of soundmedical judgment, suitable for use in contact with the tissues of humansand lower animals with undue toxicity, irritation, allergic response,and the like, commensurate with a reasonable benefit/risk ratio, andeffective for their intended use, as well as the zwitterionic forms,where possible, of the compounds of the invention. The term “prodrug”refers to compounds that are transformed in vivo to yield the parentcompound of the above formula, for example by hydrolysis in blood. Athorough discussion is provided in T. Higuchi and V. Stella, Pro-drugsas Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series, andin Edward B. Roche, ed., Bioreversible Carriers in Drug Design, AmericanPharmaceutical Association and Pergamon Press, 1987, both of which areincorporated herein by reference. Various forms of prodrugs are known inthe art, for example as discussed in Bundgaard (ed.), Design ofProdrugs, Elsevier (1985); Widder et al. (ed.), Methods in Enzymology,vol. 4, Academic Press (1985); Kgrogsgaard-Larsen et al. (ed.); “Designand Application of Prodrugs”, Textbook of Drug Design and Development,Chapter 5, 113-191 (1991); Bundgaard et al., Journal of Drug DeliveryReviews, 8:1-38 (1992); Bundgaard et al., J. Pharmaceutical Sciences,77:285 et seq. (1988); and Higuchi and Stella (eds.), Prodrugs as NovelDrug Delivery Systems, American Chemical Society (1975).

“Preservative”: As used herein, the term “preservative” has itsart-understood meaning and refers to an agent that protects againstundesirable chemical modifications of one or more components in acomposition (e.g., protection against an undesirable chemicalmodification of an active ingredient). Suitable preservatives for use inthe compositions of the present invention include, but are not limitedto, one or more alkanols, disodium EDTA, EDTA salts, EDTA fatty acidconjugates, isothioazolinone, parabens such as methylparaben andpropylparaben, polypropylene glycols, sorbates, urea derivatives such asdiazolindinyl urea, or combinations thereof.

“Propellant”: As used herein, the term “propellant” refers to an agentthat propels the delivery of a composition in, e.g., a vaporized,aerosol nebulized, or spray form. Propellants often are used inmetered-dose inhalers for the treatment of asthma and other respiratorydisorders and for systemic treatments such as insulin for diabetes.Propellants also are used, for example, in nasal inhalers for treatmentof allergic rhinitis, topical sprays, oral sprays, and other aerosolapplications. An example of such propellants, without limitation, arethe Dymel® pharmaceutical propellants manufactured by DuPont®.(Wilmington, Del.).

“Protective”: As used herein, the term “protective” refers to an agentthat isolates exposed surface of skin or other membrane from harmful orannoying stimuli. Exemplary protectives include dusting powders,adsorbents, mechanical protective agents, and plasters. Mechanicalprotectives are generally either collodions or plasters, and include,for example aluminum hydroxide gel, collodium, dimethicone, petrolatumgauze, absorbable gelatin film, absorbable gelatin sponge, zinc gelatin,kaolin, lanolin, anhydrous lanolin, mineral oil, mineral oil emulsion,mineral oil light, olive oil, peanut oil, petrolatum, silicones,hydrocolloids and the like. In some embodiments, a protective includesan adherent, continuous film that may be flexible or semi-rigiddepending on the materials and the formulations as well as the manner inwhich they are applied. In some embodiments, a “protective” may be a“demulscent” as described herein.

“Racemic”: As used herein, a racemic mixture means about 50% of oneenantiomer and about 50% of its corresponding enantiomer relative to allchiral centers in a molecule. Compounds of the present invention mayencompass enantiomerically pure, enantiomerically enriched, and racemicmixtures.

“Rubefacient”: As used herein, the term “rubefacient” is an agent thatinduces hyperemia, wherein hyperemia means an increased amount of bloodin a body part or organ. Rubefaction, which is induced by rubefacients,results from increased circulation to an injured area and is accompaniedby a feeling of comfort, warmth, itching and hyperesthesia.

“Skin Irritant”: As used herein, the term “skin irritant” refers to acompound that, when applied to skin or a skin equivalents, elicits acellular response characterized by the expression of an “irritantresponsive gene.” Examples of known skin irritants include, but are notlimited to, sodium dodecyl sulfate (“SDS”), calcipotriol, andtrans-retinoic acid. The term “skin irritant” is also intended toencompass unknown or suspected irritants, including but not limited to,those containing in some pharmaceuticals, cosmetics, and consumerproducts.

“Solubilizing agent”: As used herein, the term “solubilizing agent” arethose substances that enable solutes to dissolve. Representativeexamples of solubilizing agents that are usable in the context of thepresent invention include, without limitation, complex-formingsolubilizers (e.g., citric acid, ethylenediamine-tetraacetate, sodiummeta-phosphate, succinic acid, urea, cyclodextrin, polyvinylpyrrolidone,diethylammonium-ortho-benzoate, etc.), n-alkyl amine n-oxides,micelle-forming solubilizers (e.g., TWEEN® including TWEEN 80®), organicsolvents (e.g., acetone, phospholipids and cyclodextrins), polyoxamers,polyoxyethylene n-alkyl ethers, and polyoxyethylene sorbitan fatty acidester.

“Steroidal anti-inflammatory agent”: As used herein, the term “steroidalanti-inflammatory agent”, refers to any one of numerous compoundscontaining a 17-carbon 4-ring system and includes the sterols, varioushormones (as anabolic steroids), and glycosides. Representative examplesof steroidal anti-inflammatory drugs include, without limitation,corticosteroids such as alpha-methyl dexamethasone, amcinafel,amcinafide, beclomethasone dipropionates, beclomethasone dipropionate,betamethasone and the balance of its esters, chloroprednisone,chlorprednisone acetate, clescinolone, clobetasol valerate,clocortelone, cortisone, cortodoxone, desonide, desoxycorticosteroneacetate, desoxymethasone, dexamethasone, dexamethasone-phosphate,dichlorisone, dichlorisone, diflorasone diacetate, diflucortolonevalerate, difluorosone diacetate, diflurosone diacetate, diflurprednate,fluadrenolone, flucetonide, fluclorolone acetonide, flucloronide,flucortine butylesters, fludrocortisone, fludrocortisone,fludrocortisone, flumethasone pivalate, flunisolide, fluocinonide,fluocortolone, fluoromethalone, fluosinolone acetonide, fluperolone,fluprednidene (fluprednylidene) acetate, fluprednisolone, fluradrenoloneacetonide, fluradrenolone, flurandrenolone, halcinonide, hydrocortamate,hydrocortisone acetate, hydrocortisone butyrate, hydrocortisonevalerate, hydrocortisone cyclopentylpropionate, hydrocortisone,hydroxyltriamcinolone, medrysone, meprednisone, methylprednisolone,paramethasone, prednisolone, prednisone, triamcinolone acetonide,triamcinolone, and combinations thereof.

“Substituted”: It will be appreciated that the compounds, as describedherein, may be substituted with any number of substituents or functionalmoieties. In general, the term “substituted” whether preceded by theterm “optionally” or not, and substituents contained in formulas of thisinvention, refer to the replacement of hydrogen radicals in a givenstructure with the radical of a specified substituent. When more thanone position in any given structure may be substituted with more thanone substituent selected from a specified group, the substituent may beeither the same or different at every position. As used herein, the term“substituted” is contemplated to include all permissible substituents oforganic compounds. In a broad aspect, the permissible substituentsinclude acyclic and cyclic, branched and unbranched, carbocyclic andheterocyclic, aromatic and nonaromatic substituents of organiccompounds. Heteroatoms such as nitrogen may have hydrogen substituentsand/or any permissible substituents of organic compounds describedherein which satisfy the valencies of the heteroatoms. Furthermore, thisinvention is not intended to be limited in any manner by the permissiblesubstituents of organic compounds. Combinations of substituents andvariables envisioned by this invention are preferably those that resultin the formation of stable compounds useful in the treatment, forexample, of inflammatory diseases and/or disorders, e.g., in themodulation of a G-protein signaling cascade.

Some examples of substituents of aliphatic and other moieties ofcompounds provided by the present invention include, but are not limitedto aliphatic; heteroaliphatic; aryl (e.g., phenyl); heteroaryl;arylalkyl; heteroarylalkyl; alkoxy; aryloxy; arylthio, heteroalkoxy;heteroaryloxy; alkylthio; arylthio; heteroalkylthio; heteroarylthio; —F;—Cl; —Br; —I; —OH; —NO₂; —CN; —CF₃; —CH₂CF₃; —CHCl₂; —CH₂OH; —CH₂CH₂OH;—CH₂NH₂; —CH₂SO₂CH₃; —C(O)R_(x); —CO₂(R_(x)); —CON(R_(x))₂; —OC(O)R_(x);—OCO₂R_(x); —OCON(R_(x))₂; —N(R_(x))₂; —S(O)₂R_(x); —NR_(x)(CO)R_(x)wherein each occurrence of R_(x) independently includes, but is notlimited to, aliphatic, heteroaliphatic, aryl, heteroaryl, arylalkyl, orheteroarylalkyl, wherein any of the aliphatic, heteroaliphatic,arylalkyl, or heteroarylalkyl substituents described above and hereinmay be substituted or unsubstituted, branched or unbranched, cyclic oracyclic, and wherein any of the aryl or heteroaryl substituentsdescribed above and herein may be substituted or unsubstituted.Additional examples of generally applicable substituents are illustratedby the specific embodiments described herein.

“Stable”: As used herein, the term “stable” preferably refers to thestate of maintaining integrity of a compound over a period of time(e.g., during manufacture and/or storage).

“Substantially free of”: As used herein, the term “substantially freeof”, when used to describe a material or compound, means that thematerial or compound lacks a significant or detectable amount of adesignated substance. In some embodiments, the designated substance ispresent at a level not more than about 1%, 2%, 3%, 4% or 5% (w/w or v/v)of the material or compound.

“Surfactants”: As used herein, the term “surfactant” is a surface-activesubstance, such as a detergent. Suitable surfactants for use with theinventive compositions include, but are not limited to, sarcosinates,glutamates, sodium alkyl sulfates, ammonium alkyl sulfates, sodiumalkyleth sulfates, ammonium alkyleth sulfates, ammoniumlaureth-n-sulfates, sodium laureth-n-sulfates, isothionates,glycerylether sulfonates, sulfosuccinates and combinations thereof. Moreparticularly, an anionic surfactant is selected from the groupconsisting of sodium lauroyl sarcosinate, monosodium lauroyl glutamate,sodium alkyl sulfates, ammonium alkyl sulfates, sodium alkylethsulfates, ammonium alkyleth sulfates, and combinations thereof.

“Sun screening agent”: As used herein, a “sun screening agent” refers toan agent, when topically applied, absorbs or reflects some of the sun'sultraviolet radiation on skin exposed to sunlight, and therefore helpsprotect against sunburn. In some embodiments, a sun screening agentabsorbed in the skin may lead to an increase in reactive oxygen species.Representative examples of sun screening agents usable in the presentinvention include, without limitation, p-aminobenzoic acid and its saltsand derivatives thereof (p-dimethylaminobenzoic acid; ethyl, glyceryl,and isobutyl esters;); anthranilates (i.e., o-amino-benzoates; benzyl,cyclohexenyl, linalyl, menthyl, methyl, phenyl, phenylethyl, andterpinyl esters); benzophenones (i.e., hydroxy- or methoxy-substitutedbenzophenones such as benzoresorcinol, butylmethoxydibenzoylmethane,2,2′-dihydroxy-4,4′-dimethoxybenzophenone, etocrylene,4-isopropyldibenzoylmethane, dioxybenzone,3-4′-methylbenzylidene-boman-2-one, octabenzone, octocrylene,oxybenzene, sulisobenzone, and 2,2′,4,4′-tetrahydroxybenzophenone);(butyl carbotol) (6-propyl piperonyl) ether; cinnamic acid derivatives(alpha.-phenyl cinnamonitrile; butyl cinnamoyl pyruvate; benzyl andmethyl esters); diazoles (2-acetyl-3-bromoindazole, aryl benzothiazoles,methyl naphthoxazole, and phenyl benzoxazole); dibenzylacetone;dihydroxycinnamic acid derivatives (methylaceto-umbelliferone,methylumbelliferone, umbelliferone); di-hydroxynaphthoic acid and itssalts; hydrocarbons (diphenylbutadiene, and stilbene); hydroquinone; o-and p-hydroxybiphenyldisulfona-tes; coumarin derivatives (3-phenyl,7-hydroxy, and 7-methyl,); naphtholsulfonates (sodium salts of2-naphthol-3,6-disulfonic and of 2-naphthol-6,8-disulfonic acids);quinine salts (bisulfate, chloride, oleate, sulfate and tannate);quinoline derivatives (8-hydroxyquinoline salts, and 2-phenylquinoline);salicylates (amyl, benzyl, di-propylene glycol, glyceryl, menthyl,octyl, and phenyl esters); tannic acid and its derivatives (e.g.,hexaethylether); trihydroxy-cinnamic acid derivatives (daphnetin,daphnin, esculetin, esculin, methylesculetin; and the glucosides); anduric and violuric acids; and combinations thereof.

“Thickeners”: As used herein, the term “thickener” refers to agents thatmake a composition more dense or viscous in consistency. Suitablethickeners that can be used in the context of the present inventioninclude, for example, non-ionic water-soluble polymers such ashydroxyethylcellulose (commercially available under the TrademarkNatrosol® 250 or 350), cationic water-soluble polymers such as Polyquat37 (commercially available under the Trademark Synthalen® CN), fattyalcohols, fatty acids, anionic polymers, and their alkali salts andmixtures thereof.

“Thio”: As used herein, the term “thio” used alone or as part of alarger moiety as in “alkylthio”, “arylthio”, “heteroalkylthio”, or“heteroarylthio” refers to replacement of an oxygen. For example,“alkylthio” refers to an alkyl group, as previously defined, attached tothe parent molecule through a sulfur atom. Similarly, “arylthio” refersto an aryl group, as previously defined, attached to the parent moleculethrough a sulfur molecule. Similarly, “heteroalkylthio” refers to aheteroalkyl group, as previously defined, attached to the parentmolecule through a sulfur molecule, etc.

“Treat,” “treating” and “treatment”: As used herein, the terms “treat,”“treating” and “treatment,” contemplate an action that occurs while apatient is suffering from or susceptible to a specified disease,disorder or condition, which delays onset of and/or reduces thefrequency or severity of one or more symptoms or features of the diseasedisorder or condition. Thus, “treat”, “treating”, and “treatment” referto any type of treatment that imparts a benefit to a subject afflictedwith a disease, disorder or condition, including improvement in thecondition of the subject (e.g., in one or more symptoms), delay in theprogression of the disease, disorder or condition, prevention or delayof the onset of the disease, disorder or condition, etc.

Unit dosage form: The expression “unit dosage form” as used hereinrefers to a physically discrete unit of a provided formulationappropriate for the subject to be treated. It will be understood,however, that the total daily usage of provided formulation will bedecided by the attending physician within the scope of sound medicaljudgment. The specific effective dose level for any particular subjector organism may depend upon a variety of factors including the disorderbeing treated and the severity of the disorder; activity of specificactive agent employed; specific formulation employed; age, body weight,general health, sex and diet of the subject; time of administration, andrate of excretion of the specific active agent employed; duration of thetreatment; drugs and/or additional therapies used in combination orcoincidental with specific compound(s) employed, and like factors wellknown in the medical arts. In some embodiments, a unit dosage formcontains an amount of a therapeutically active agent appropriate for usein a therapeutic regimen (i.e., in a regimen that delivers atherapeutically effective amount of an agent). In some embodiments, sucha unit dosage form may be considered to contain a “therapeuticallyeffective amount” of an agent even if a single dose would not beexpected to be effective.

“Unsaturated”: As used herein, the term “unsaturated” means that amoiety has one or more units of unsaturation.

“Vitamin”: As used herein, the term “vitamin” refers to any of variousorganic substances essential in minute quantities to the nutrition ofmost animals act especially as coenzymes and precursors of coenzymes inthe regulation of metabolic processes. Non-limiting examples of vitaminsusable in context of the present invention include vitamin A and itsanalogs and derivatives: retinol, retinal, retinyl palmitate, retinoicacid, tretinoin, iso-tretinoin (known collectively as retinoids),vitamin E (tocopherol and its derivatives), vitamin C (L-ascorbic acidand its esters and other derivatives), vitamin B₃ (niacinamide and itsderivatives), alpha hydroxy acids (such as glycolic acid, lactic acid,tartaric acid, malic acid, citric acid, etc.) and beta hydroxy acids(such as salicylic acid and the like).

1. Description of Certain Exemplary Compounds

Presently disclosed compounds provided by the present invention includethose described generally above, and are further illustrated by allclasses, subclasses and species of each of these compounds disclosedherein.

In one embodiment, presently disclosed compounds include those compoundsencompassed by the formula:

or a pharmaceutically acceptable salt, solvate, prodrug or esterthereof;wherein:X is —C(O)— or a covalent bond;Y is hydroxyl, —NH₂, —O—C₁-C₅ alkyl or C₁-C₅ alkyl;A and B are independently selected from NR, N(C₁-C₅ alkyl), N(C₁-C₅alkylene)-R, N(C₁-C₅ alkylene)-CN, N(C₁-C₅ alkylene carboxyl), each ofsaid alkyl or alkylene group optionally substituted with one or more Rgroups, —O—, a R-substituted or unsubstituted C₁-C₅ alkylene, aR-substituted or unsubstituted O—C₁-C₅ alkylene, a R-substituted orunsubstituted arylene or a R-substituted or unsubstituted heteroarylenehaving 1-4 heteroatoms independently selected from nitrogen, oxygen, orsulfur, or a R-substituted or unsubstituted C₃-C₆ cycloalkylene orR-substituted or unsubstituted C₃-C₆ heterocycloalkylene having 1-4heteroatoms independently selected from nitrogen, oxygen or sulfur;or A and B together form a R-substituted or unsubstituted arylene or aR-substituted or unsubstituted heteroarylene having 1-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or aR-substituted or unsubstituted C₃-C₆ cycloalkylene or R-substituted orunsubstituted C₃-C₆ heterocycloalkylene having 1-4 heteroatomsindependently selected from nitrogen, oxygen or sulfur;D is —OH or —O(C₁-C₅ alkyl); andE and E′ are independently selected from H and C₁-C₅ alkyl;R is, independently, H, C₁-C₅ alkyl, OH, S(C₁-C₅ alkyl), NH(C₁-C₅alkyl), NH(C₁-C₅ alkylene carboxyl), NH(C₁-C₅ alkylene guanidine),N(C₁-C₅ alkylene amidine), N(C₁-C₅ alkylene amide), CF₃, —CN, —COOH orO(C₁-C₅ alkyl); and

Z is a substituted or unsubstituted, branched or unbranched, saturatedor unsaturated, C₁₀-C₂₅ aliphatic;

provided that when A and B are both —CH₂—, D is hydroxyl, X is —C(O)—and E is hydrogen, Y cannot be hydroxyl, —OCH₃ or —CH₃.

In one embodiment, presently disclosed compounds include those compoundsencompassed by the formula:

or a pharmaceutically acceptable salt, solvate, prodrug or esterthereof;wherein:X is —C(O)— or a covalent bond;Y is hydroxyl, —NH₂, —O—C₁-C₅ alkyl or C₁-C₅ alkyl;A and B are independently selected from NR, N(C₁-C₅ alkyl), N(C₁-C₅alkylene)-R, N(C₁-C₅ alkylene)-CN, N(C₁-C₅ alkylene carboxyl), each ofsaid alkyl or alkylene group optionally substituted with one or more Rgroups, —O—, a R-substituted or unsubstituted C₁-C₅ alkylene, aR-substituted or unsubstituted O—C₁-C₅ alkylene, a R-substituted orunsubstituted arylene or a R-substituted or unsubstituted heteroarylenehaving 1-4 heteroatoms independently selected from nitrogen, oxygen orsulfur, or a R-substituted or unsubstituted C₃-C₆ cycloalkylene orR-substituted or unsubstituted C₃-C₆ heterocycloalkylene having 1-4heteroatoms independently selected from nitrogen, oxygen or sulfur;or A and B together form a R-substituted or unsubstituted arylene or aR-substituted or unsubstituted heteroarylene having 1-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or aR-substituted or unsubstituted C₃-C₆ cycloalkylene or R-substituted orunsubstituted C₃-C₆ heterocycloalkylene having 1-4 heteroatomsindependently selected from nitrogen, oxygen or sulfur;D is —OH or —O(C₁-C₅ alkyl);E and E′ are independently selected from H and C₁-C₅ alkyl;R is, independently, H, C₁-C₅ alkyl, OH, S(C₁-C₅ alkyl), NH(C₁-C₅alkyl), NH(C₁-C₅ alkylene carboxyl), NH(C₁-C₅ alkylene guanidine),N(C₁-C₅ alkylene amidine), N(C₁-C₅ alkylene amide), CF₃, —CN, —COOH orO(C₁-C₅ alkyl);provided that when A and B are both —CH₂—, D is hydroxyl, X is —C(O)—and E is hydrogen, Y cannot be hydroxyl, —OCH₃ or —CH₃.

In one embodiment, presently disclosed compounds include those compoundsencompassed by the formula:

or a pharmaceutically acceptable salt, solvate, prodrug or esterthereof;wherein:Y is hydroxyl, —NH₂, —O—C₁-C₅ alkyl or C₁-C₅ alkyl;A and B are independently selected from NR, N(C₁-C₅ alkyl), N(C₁-C₅alkylene)-R, N(C₁-C₅ alkylene)-CN, N(C₁-C₅ alkylene carboxyl), each ofsaid alkyl or alkylene group optionally substituted with one or more Rgroups, —O—, a R-substituted or unsubstituted C₁-C₅ alkylene, aR-substituted or unsubstituted O—C₁-C₅ alkylene, a R-substituted orunsubstituted arylene or a R-substituted or unsubstituted heteroarylenehaving 1-4 heteroatoms independently selected from nitrogen, oxygen orsulfur, or a R-substituted or unsubstituted C₃-C₆ cycloalkylene orR-substituted or unsubstituted C₃-C₆ heterocycloalkylene having 1-4heteroatoms independently selected from nitrogen, oxygen or sulfur;or A and B together form a R-substituted or unsubstituted arylene or aR-substituted or unsubstituted heteroarylene having 1-4 heteroatomsindependently selected from nitrogen, oxygen or sulfur, or aR-substituted or unsubstituted C₃-C₆ cycloalkylene or R-substituted orunsubstituted C₃-C₆ heterocycloalkylene having 1-4 heteroatomsindependently selected from nitrogen, oxygen or sulfur;R is, independently, H, C₁-C₅ alkyl, OH, S(C₁-C₅ alkyl), NH(C₁-C₅alkyl), NH(C₁-C₅ alkylene carboxyl), NH(C₁-C₅ alkylene guanidine),N(C₁-C₅ alkylene amidine), N(C₁-C₅ alkylene amide), CF₃, —CN, —COOH orO(C₁-C₅ alkyl); andZ is a substituted or unsubstituted, branched or unbranched, saturatedor unsaturated, C₁₀-C₂₅ aliphatic;provided that when A and B are both —CH₂—, Y cannot be hydroxyl, —OCH₃or —CH₃.

In one embodiment, Z is selected from a farnesyl or phytyl group. In oneembodiment, Z is a farnesyl group. In one embodiment, Z is a phytylgroup.

In one embodiment, presently disclosed compounds include those compoundsencompassed by the formula:

or a pharmaceutically acceptable salt, solvate, prodrug or esterthereof;wherein:Y is hydroxyl, —NH₂, —O—C₁-C₅ alkyl or C₁-C₅ alkyl;A and B are independently selected from NR, N(C₁-C₅ alkyl), N(C₁-C₅alkylene)-R, N(C₁-C₅ alkylene)-CN, N(C₁-C₅ alkylene carboxyl), each ofsaid alkyl or alkylene group optionally substituted with one or more Rgroups, —O—, a R-substituted or unsubstituted C₁-C₅ alkylene, aR-substituted or unsubstituted O—C₁-C₅ alkylene, a R-substituted orunsubstituted arylene or a R-substituted or unsubstituted heteroarylenehaving 1-4 heteroatoms independently selected from nitrogen, oxygen orsulfur, or a R-substituted or unsubstituted C₃-C₆ cycloalkylene orR-substituted or unsubstituted C₃-C₆ heterocycloalkylene having 1-4heteroatoms independently selected from nitrogen, oxygen or sulfur;or A and B together form a R-substituted or unsubstituted arylene or aR-substituted or unsubstituted heteroarylene having 1-4 heteroatomsindependently selected from nitrogen, oxygen or sulfur, or aR-substituted or unsubstituted C₃-C₆ cycloalkylene or R-substituted orunsubstituted C₃-C₆ heterocycloalkylene having 1-4 heteroatomsindependently selected from nitrogen, oxygen or sulfur;R is, independently, H, C₁-C₅ alkyl, OH, S(C₁-C₅ alkyl), NH(C₁-C₅alkyl), NH(C₁-C₅ alkylene carboxyl), NH(C₁-C₅ alkylene guanidine),N(C₁-C₅ alkylene amidine), N(C₁-C₅ alkylene amide) or O(C₁-C₅ alkyl);provided that when A and B are both —CH₂—, Y cannot be hydroxyl, —OCH₃or —CH₃.

In one embodiment, the presently disclosed compounds include thosecompounds encompassed by the formula:

or a pharmaceutically acceptable salt, solvate, prodrug or esterthereof;wherein:Y is hydroxyl, —NH₂, —O—C₁-C₅ alkyl or C₁-C₅ alkyl;A and B together form a R-substituted or unsubstituted arylene or aR-substituted or unsubstituted heteroarylene having 1-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or aR-substituted or unsubstituted C₃-C₆ cycloalkylene or R-substituted orunsubstituted C₃-C₆ heterocycloalkylene having 1-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur;D is —OH or —O(C₁-C₅ alkyl);E and E′ are independently selected from H and C₁-C₅ alkyl; andR is, independently, H, C₁-C₅ alkyl, OH, S(C₁-C₅ alkyl), NH(C₁-C₅alkyl), NH(C₁-C₅ alkylene carboxyl), NH(C₁-C₅ alkylene guanidine),N(C₁-C₅ alkylene amidine), N(C₁-C₅ alkylene amide), CF₃, —CN, —COOH, orO(C₁-C₅ alkyl).

In one embodiment, presently disclosed compounds include those compoundsencompassed by the formula:

or a pharmaceutically acceptable salt, solvate, prodrug or esterthereof;wherein:Y is hydroxyl, —NH₂, —O—C₁-C₅ alkyl or C₁-C₅ alkyl;A is selected from R, C₁-C₅ alkyl, (C₁-C₅ alkylene)-R, (C₁-C₅alkylene)-CN, (C₁-C₅ alkylene)-carboxyl, each of said alkyl or alkylenegroup optionally substituted with one or more R groups;B is an unsubstituted C₁-C₂ alkylene;or A, B and the nitrogen atom bound to A and B form a R-substituted orunsubstituted C₃-C₆ heterocycloalkylene having 1-4 heteroatomsindependently selected from nitrogen, oxygen or sulfur; andR is, independently, H, C₁-C₅ alkyl, OH, S(C₁-C₅ alkyl), NH(C₁-C₅alkyl), NH(C₁-C₅ alkylene carboxyl), NH(C₁-C₅ alkylene guanidine),N(C₁-C₅ alkylene amidine), N(C₁-C₅ alkylene amide), CF₃, —CN, —COOH orO(C₁-C₅ alkyl).

In one embodiment, presently disclosed compounds include those compoundsencompassed by the formula:

or a pharmaceutically acceptable salt, solvate, prodrug or esterthereof;wherein:Y is hydroxyl, —NH₂, —O—C₁-C₅ alkyl or C₁-C₅ alkyl;A is an unsubstituted C₁-C₂ alkylene;B is selected from R, C₁-C₅ alkyl, (C₁-C₅ alkylene)-R, (C₁-C₅alkylene)-CN, (C₁-C₅ alkylene)-carboxyl, each of said alkyl or alkylenegroup optionally substituted with one or more R groups;or A, B and the nitrogen atom bound to A and B form a R-substituted orunsubstituted C₃-C₆ heterocycloalkylene having 1-4 heteroatomsindependently selected from nitrogen, oxygen or sulfur; andR is, independently, H, C₁-C₅ alkyl, OH, S(C₁-C₅ alkyl), NH(C₁-C₅alkyl), NH(C₁-C₅ alkylene carboxyl), NH(C₁-C₅ alkylene guanidine),N(C₁-C₅ alkylene amidine), N(C₁-C₅ alkylene amide), CF₃, —CN, —COOH orO(C₁-C₅ alkyl).

In one embodiment, presently disclosed compounds include those compoundsencompassed by the formula:

or a pharmaceutically acceptable salt, solvate, prodrug or esterthereof;wherein:Y is hydroxyl, —NH₂, —O—C₁-C₅ alkyl or C₁-C₅ alkyl;A is NH, N(C₁-C₅ alkyl), N(C₁-C₅ alkylene carboxyl) or a R-substitutedor unsubstituted C₁-C₅ alkylene;B is NH, N(C₁-C₅ alkyl), N(C₁-C₅ alkylene carboxyl) or a R-substitutedor unsubstituted C₁-C₅ alkylene;or A and B together form a R-substituted or unsubstituted arylene or aR-substituted or unsubstituted heteroarylene having 1-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or aR-substituted or unsubstituted C₃-C₆ cycloalkylene or R-substituted orunsubstituted C₃-C₆ heterocycloalkylene having 1-4 heteroatomsindependently selected from nitrogen, oxygen or sulfur;R is, independently, C₁-C₅ alkyl, OH, S(C₁-C₅ alkyl), NH(C₁-C₅ alkyl),NH(C₁-C₅ alkylene carboxyl), NH(C₁-C₅ alkylene guanidine), N(C₁-C₅alkylene amidine), N(C₁-C₅ alkylene amide) or O(C₁-C₅ alkyl); andZ is is a substituted or unsubstituted, branched or unbranched,saturated or unsaturated, C₁₀-C₂₅ aliphatic;provided that when A and B are both —CH₂—, Y cannot be hydroxyl, —OCH₃or —CH₃.

In one embodiment, Z is selected from a farnesyl or phytyl group. In oneembodiment, Z is a farnesyl group. In one embodiment, Z is a phytylgroup.

In one embodiment, presently disclosed compounds include those compoundsencompassed by the formula:

or a pharmaceutically acceptable salt, solvate, prodrug or esterthereof;wherein:Y is hydroxyl, —NH₂, —O—C₁-C₅ alkyl or C₁-C₅ alkyl;A is NH, N(C₁-C₅ alkyl), N(C₁-C₅ alkylene carboxyl) or a R-substitutedor unsubstituted C₁-C₅ alkylene;B is NH, N(C₁-C₅ alkyl), N(C₁-C₅ alkylene carboxyl) or a R-substitutedor unsubstituted C₁-C₅ alkylene;or A and B together form a R-substituted or unsubstituted arylene or aR-substituted or unsubstituted heteroarylene having 1-4 heteroatomsindependently selected from nitrogen, oxygen or sulfur, or aR-substituted or unsubstituted C₃-C₆ cycloalkylene or R-substituted orunsubstituted C₃-C₆ heterocycloalkylene having 1-4 heteroatomsindependently selected from nitrogen, oxygen or sulfur;R is, independently, C₁-C₅ alkyl, OH, S(C₁-C₅ alkyl), NH(C₁-C₅ alkyl),NH(C₁-C₅ alkylene carboxyl), NH(C₁-C₅ alkylene guanidine), N(C₁-C₅alkylene amidine), N(C₁-C₅ alkylene amide) or O(C₁-C₅ alkyl);provided that when A and B are both —CH₂—, Y cannot be hydroxyl, —OCH₃or —CH₃.

In one embodiment, presently disclosed compounds include those compoundsencompassed by the formula:

or a pharmaceutically acceptable salt, solvate, prodrug or esterthereof;wherein:Y is hydroxyl, —NH₂, —O—C₁-C₅ alkyl or C₁-C₅ alkyl;A is hydrogen, an unsubstituted C₁-C₂ alkyl or CH₂COOH;B is an unsubstituted C₁-C₂ alkylene;or A, B and the nitrogen atom bound to A and B form a R-substituted orunsubstituted C₃-C₆ heterocycloalkylene having 1-4 heteroatomsindependently selected from nitrogen, oxygen or sulfur; andR is C₁-C₅ alkyl, OH, S(C₁-C₅ alkyl), NH(C₁-C₅ alkyl), NH(C₁-C₅ alkylenecarboxyl), NH(C₁-C₅ alkylene guanidine), N(C₁-C₅ alkylene amidine),N(C₁-C₅ alkylene amide) or O(C₁-C₅ alkyl).

In one embodiment, presently disclosed compounds include those compoundsencompassed by the formula:

or a pharmaceutically acceptable salt, solvate, prodrug or esterthereof;wherein:Y is hydroxyl, —NH₂, —O—C₁-C₅ alkyl or C₁-C₅ alkyl;A is an unsubstituted C₁-C₂ alkylene;B is hydrogen, an unsubstituted C₁-C₂ alkyl or CH₂COOH;or A, B and the nitrogen atom bound to A and B form a R-substituted orunsubstituted C₃-C₆ heterocycloalkylene having 1-4 heteroatomsindependently selected from nitrogen, oxygen or sulfur; andR is C₁-C₅ alkyl, OH, S(C₁-C₅ alkyl), NH(C₁-C₅ alkyl), NH(C₁-C₅ alkylenecarboxyl), NH(C₁-C₅ alkylene guanidine), N(C₁-C₅ alkylene amidine),N(C₁-C₅ alkylene amide) or O(C₁-C₅ alkyl).

In one embodiment, presently disclosed compounds include those compoundsset forth below in Table 1, or a pharmaceutically acceptable salt,solvate, prodrug or ester thereof.

Table 1. Exemplary Compounds

In certain embodiments, the presently disclosed compounds include anyone, or any combination of, the exemplary compounds disclosed below, andpharmaceutically acceptable salts, solvates, prodrugs or esters thereof:

In one embodiment, the presently disclosed compound is compound C, or apharmaceutically acceptable salt, solvate, prodrug or ester thereof. Inone embodiment, the presently disclosed compound is compound E, or apharmaceutically acceptable salt, solvate, prodrug or ester thereof. Inone embodiment, the presently disclosed compound is compound G, or apharmaceutically acceptable salt, solvate, prodrug or ester thereof.

In one embodiment, compound E, or a pharmaceutically acceptable salt,solvate, prodrug or ester thereof, is excluded as a presently disclosedcompound of the present invention. In one embodiment, compound G, or apharmaceutically acceptable salt, solvate, prodrug or ester thereof, isexcluded as a presently disclosed compound of the present invention.

Unless otherwise stated, all tautomeric forms of the presently disclosedcompounds are within the scope of the invention. Additionally, unlessotherwise stated, structures depicted herein are also meant to includecompounds that differ only in the presence of one or more isotopicallyenriched atoms. For example, compounds having the present structuresincluding the replacement of hydrogen by deuterium or tritium, or thereplacement of a carbon by a ¹³C- or ¹⁴C-enriched carbon are within thescope of this invention. Such compounds are useful, for example, asanalytical tools, as probes in biological assays, or as therapeuticagents in accordance with the present invention. Mixtures of isomericforms may be separated and/or purified by techniques as would be knownto one skilled in this art, including but not limited to columnchromatography.

The presently disclosed compounds may be provided according to thepresent invention in any of a variety of useful forms, for example aspharmaceutically acceptable salts, as particular crystal forms, etc. Insome embodiments, prodrugs of one or more compounds of the presentinvention are provided.

In certain embodiments, provided compounds modulate a G-proteinsignaling cascade. In certain embodiments, provided compounds alter theinteractions among polyisoprenylated signal transduction proteins, suchas G-proteins and the protein regulatory targets with which theyinteract, or other intracellular signaling proteins. In certainembodiments, provided compounds modulate the inflammatory response. Incertain embodiments, provided compounds inhibit inflammation and aretherefore anti-inflammatory.

In some embodiments, provided compounds modulate levels of inflammatorymediators, such as cytokines induced by G-protein-mediated pathways(e.g., purinergic receptors). In some embodiments, provided compoundsinhibit the levels of proinflammatory mediators, such as proinflammatorycytokines. In further embodiments, provided compounds inhibit levels ofproinflammatory mediators, such as proinflammatory cytokines induced byG-protein-mediated pathways.

In some embodiments, provided compounds modulate levels of inflammatorymediators, such as cytokines induced by other signal transductionpathways [e.g., pathways involving Toll-like receptors (“TLRs”) and TNFαreceptors]. In some embodiments, provided compounds inhibit levels ofproinflammatory mediators, such as proinflammatory cytokines induced byother signal transduction pathways [e.g., pathways involving Toll-likereceptors (“TLRs”) and TNFα receptors].

In some embodiments, provided compounds inhibit levels ofproinflammatory mediators, such as proinflammatory cytokines that areinduced by chemicals such as TPA.

In some embodiments, provided compounds modulate the levels ofinflammatory mediators such as cytokines characterized using anovalbumin-induced flaky tail Atopic Dermatis mouse model.

In some embodiments, the presently disclosed compounds modulate theinfiltration and accumulation of T-helper lymphocytes. In someembodiments, the presently disclosed compounds modulate T-helperlymphocytes with CD3+ marker. In some embodiments, the presentlydisclosed compounds modulate the infiltration and accumulation ofT-helper lymphocytes characterized using a Stat3c psoriasis mouse model.In some embodiments, the presently disclosed compounds inhibitinfiltration and accumulation of T-helper lymphocytes. In someembodiments, the presently disclosed compounds inhibit infiltration andaccumulation of T-helper lymphocytes with CD3+ marker. In someembodiments, the presently disclosed compounds inhibit infiltration andaccumulation of T-helper lymphocytes characterized using a Stat3cpsoriasis mouse model.

In some embodiments, the presently disclosed compounds inhibitmethylesterifcation reactions by a specific membrane associatedS-adenosylmethionine-dependent isoprenyl-S-isoprenyl methyltransferase(“ICMT”) resulting in carboxy-terminal polyisoprenoid cysteinemodifications of a number of key factors in G-protein signaling pathway.

In some embodiments, the presently disclosed compounds inhibit oxidativeburst from neutrophils and are therefore anti-oxidants.

In certain embodiments, activity of provided compounds may becharacterized using a variety of in vitro or in vivo assays, involving avariety of cell-based or animal-based models. For example, data fromexemplary assays for: Edema, Erythema and/or Inhibition ofMyeloperoxidase; Inflammatory Cytokines; Stat3c-Psoriasis Mouse Model;Inhibition of Methylesterification Reactions; and Inhibition ofOxidative Burst are each described below.

Edema, Erythema and/or Inhibition of Myeloperoxidase (MPO)

Ability of provided compounds to modulate inflammatory responses may beassessed, for example, using assays that assess edema, erythema, and/orinhibition of myeloperoxidase (“MPO”) as described, for example, inExample 79 of U.S. Published Application No. 2016/0361283, which ishereby incorporated by reference in its entirety.

In certain embodiments, the presently disclosed compounds are consideredto be inhibitors of inflammation when they show a percent inhibition inan edema assay of at least about 30%, about 35%, about 40%, about 50%,about 60%, about 70%, about 80%, about 90 or about 95%, for example whenprovided at a dose of or about 0.2 mg/20 μl, or at a dose of or about0.8 mg/20 μL. In certain embodiments, the presently disclosed compoundsare considered to be inhibitors of inflammation when they result in anED₅₀ in an edema assay of at least about 0.5, about 1, about 1.5, about2, about 2.5, about 3, about 3.5, about 4, or about 4.5-fold lower thanthat observed with AFC.

In certain embodiments, the presently disclosed compounds are consideredto be inhibitors of inflammation when they show a percent inhibition inan erythema assay of at least about 25%, about 30%, about 35%, about40%, about 50%, about 60%, about 70%, about 80%, about 90% or about 95%,for example when provided at a dose of or about 02. mg/20 μl, or at adose of or about 0.8 mg/20 μL. In certain embodiments, the presentlydisclosed compounds are considered to be inhibitors of inflammation whenthey result in an ED₅₀ in an erythema assay of at least about 0.5, about1, about 1.5, about 2, about 2.5, about 3, about 3.5, about 4, or about4.5-fold lower than that observed with AFC.

In certain embodiments, the presently disclosed compounds are consideredto be inhibitors of inflammation when they show a percent inhibition inan MPO activity assay of at least about 25%, about 30%, about 35%, about40%, about 50%, about 60%, about 70%, about 80%, about 90% or about 95%,for example when provided at a dose of or about 02. mg/20 μl, or at adose of or about 0.8 mg/20 μL. In certain embodiments, the presentlydisclosed compounds are considered to be inhibitors of inflammation whenthey result in an ED₅₀ in an MPO activity assay of at least about 0.5,about 1, about 1.5, about 2, about 2.5, about 3, about 3.5, about 4, orabout 4.5-fold lower than that observed with AFC.

Inflammatory Cytokines (i) TPA-Induced Mouse Ear Inflammatory Model

In certain embodiments, the presently disclosed compounds are consideredinhibitors of inflammation when they show a percent inhibition ofcytokine release in a TPA-induced mouse ear inflammatory model of atleast about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75,80, 85, 90 or 95%, for example when provided at a dosage of 0.25%. Incertain embodiments, the presently disclosed compounds are consideredinhibitors of inflammation when they result in an ED₅₀ in a TPA-inducedmouse ear inflammatory model of at least about 0.01, 0.05, 0.10, 0.15,0.20, 0.25, 0.30, 0.35 or 0.40 μg cytokine/mouse ear, for example whenprovided at a dosage of 0.25%. In certain embodiments, the presentlydisclosed compounds are considered inhibitors of inflammation when theyshow a percent inhibition of cytokine release in a TPA-induced mouse earinflammatory model of at least about 5, 10, 15, 20, 25, 30, 35, 40, 45,50, 55, 60, 65, 70, 75, 80, 85, 90 or 95%, for example when provided ata dosage of 0.50%. In certain embodiments, the presently disclosedcompounds are considered inhibitors of inflammation when they result inan ED₅₀ in a TPA-induced mouse ear inflammatory model of at least about0.01, 0.05, 0.10, 0.15, 0.20, 0.25, 0.30, 0.35 or 0.40 μg cytokine/mouseear, for example when provided at a dosage of 0.50%. In certainembodiments, the presently disclosed compounds are considered inhibitorsof inflammation when they show a percent inhibition of cytokine releasein a TPA-induced mouse ear inflammatory model of at least about 5, 10,15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90 or 95%,for example when provided at a dosage of 1.00%. In certain embodiments,the presently disclosed compounds are considered inhibitors ofinflammation when they result in an ED₅₀ in a TPA-induced mouse earinflammatory model of at least about 0.01, 0.05, 0.10, 0.15, 0.20, 0.25,0.30, 0.35 or 0.40 μg cytokine/mouse ear, for example, when provided ata dosage of 1.00%.

(ii) LPS-TLR4-Induced Cytokine Release Inflammatory Model

In certain embodiments, the presently disclosed compounds are consideredinhibitors of inflammation when they show a percent inhibition ofcytokine release in a LPS-TLR4-induced cytokine release model, asdetermined using HMEC-1 cells of at least about 5, 10, 15, 20, 25, 30,35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90 or 95%, for example whenprovided at a dosage of 0.25%. In certain embodiments, the presentlydisclosed compounds are considered inhibitors of inflammation when theyresult in an ED₅₀ in a LPS-TLR4-induced cytokine release model, asdetermined using HMEC-1 cells, of at least about 0.01, 0.05, 0.10, 0.15,0.20, 0.25, 0.30, 0.35 or 0.40 μg cytokine/mouse ear, for example whenprovided at a dosage of 0.25%. In certain embodiments, the presentlydisclosed compounds are considered inhibitors of inflammation when theyshow a percent inhibition of cytokine release in a LPS-TLR4-inducedcytokine release model, as determined using HMEC-1 cells, of at leastabout 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85,90 or 95%, for example when provided at a dosage of 0.50%. In certainembodiments, the presently disclosed compounds are considered inhibitorsof inflammation when they result in an ED₅₀ in a LPS-TLR4-inducedcytokine release model, as determined using HMEC-1 cells, of at leastabout 0.01, 0.05, 0.10, 0.15, 0.20, 0.25, 0.30, 0.35 or 0.40 μgcytokine/mouse ear, for example when provided at a dosage of 0.50%. Incertain embodiments, the presently disclosed compounds are consideredinhibitors of inflammation when they show a percent inhibition ofcytokine release in a LPS-TLR4-induced cytokine release model, asdetermined using HMEC-1 cells, of at least about 5, 10, 15, 20, 25, 30,35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90 or 95%, for example whenprovided at a dosage of 1.00%. In certain embodiments, the presentlydisclosed compounds are considered inhibitors of inflammation when theyresult in an ED₅₀ in a LPS-TLR4-induced cytokine release model, asdetermined using HMEC-1 cells, of at least about 0.01, 0.05, 0.10, 0.15,0.20, 0.25, 0.30, 0.35 or 0.40 μg cytokine/mouse ear, for example, whenprovided at a dosage of 1.00%.

(iii) TPA-Induced Cytokine Release Inflammatory Model

In certain embodiments, the presently disclosed compounds are consideredinhibitors of inflammation when they show a percent inhibition ofcytokine release in a TPA-induced cytokine release model, as determinedusing NHEK cells of at least about 5, 10, 15, 20, 25, 30, 35, 40, 45,50, 55, 60, 65, 70, 75, 80, 85, 90 or 95%, for example when provided ata dosage of 0.25%. In certain embodiments, the presently disclosedcompounds are considered inhibitors of inflammation when they result inan ED₅₀ in a TPA-induced cytokine release model, as determined usingNHEK cells, of at least about 0.01, 0.05, 0.10, 0.15, 0.20, 0.25, 0.30,0.35 or 0.40 μg cytokine/mouse ear, for example when provided at adosage of 0.25%. In certain embodiments, the presently disclosedcompounds are considered inhibitors of inflammation when they show apercent inhibition of cytokine release in a TPA-induced cytokine releasemodel, as determined using NHEK cells, of at least about 5, 10, 15, 20,25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90 or 95%, forexample when provided at a dosage of 0.50%. In certain embodiments, thepresently disclosed compounds are considered inhibitors of inflammationwhen they result in an ED₅₀ in a TPA-induced cytokine release model, asdetermined using NHEK cells, of at least about 0.01, 0.05, 0.10, 0.15,0.20, 0.25, 0.30, 0.35 or 0.40 μg cytokine/mouse ear, for example whenprovided at a dosage of 0.50%. In certain embodiments, the presentlydisclosed compounds are considered inhibitors of inflammation when theyshow a percent inhibition of cytokine release in a TPA-induced cytokinerelease model, as determined using NHEK cells, of at least about 5, 10,15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90 or 95%,for example when provided at a dosage of 1.00%. In certain embodiments,the presently disclosed compounds are considered inhibitors ofinflammation when they result in an ED₅₀ in a TPA-induced cytokinerelease model, as determined using NHEK cells, of at least about 0.01,0.05, 0.10, 0.15, 0.20, 0.25, 0.30, 0.35 or 0.40 μg cytokine/mouse ear,for example, when provided at a dosage of 1.00%.

(iv) Ovalbumin-Induced Atopic Dermatis Mouse Model

In certain embodiments, the presently disclosed compounds are consideredinhibitors of inflammation when they show a percent inhibition ofcytokine release in an Ovalbumin-induced Atopic Dermatitis mouse model,of at least about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70,75, 80, 85, 90 or 95%, for example when provided at a dosage of 0.25%.In certain embodiments, the presently disclosed compounds are consideredinhibitors of inflammation when they result in an ED₅₀ in anOvalbumin-induced Atopic Dermatitis mouse model, of at least about 0.01,0.05, 0.10, 0.15, 0.20, 0.25, 0.30, 0.35 or 0.40 μg cytokine/mouse ear,for example when provided at a dosage of 0.25%.

In certain embodiments, the presently disclosed compounds are consideredinhibitors of inflammation when they show a percent inhibition ofcytokine release in an Ovalbumin-induced Atopic Dermatitis mouse model,of at least about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70,75, 80, 85, 90 or 95%, for example when provided at a dosage of 0.50%.In certain embodiments, the presently disclosed compounds are consideredinhibitors of inflammation when they result in an ED₅₀ in anOvalbumin-induced Atopic Dermatitis mouse model, of at least about 0.01,0.05, 0.10, 0.15, 0.20, 0.25, 0.30, 0.35 or 0.40 μg cytokine/mouse ear,for example when provided at a dosage of 0.50%. In certain embodiments,the presently disclosed compounds are considered inhibitors ofinflammation when they show a percent inhibition of cytokine release inan Ovalbumin-induced Atopic Dermatitis mouse model, of at least about 5,10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90 or95%, for example when provided at a dosage of 1.00%. In certainembodiments, the presently disclosed compounds are considered inhibitorsof inflammation when they result in an ED₅₀ in an Ovalbumin-inducedAtopic Dermatitis mouse model, of at least about 0.01, 0.05, 0.10, 0.15,0.20, 0.25, 0.30, 0.35 or 0.40 μg cytokine/mouse ear, for example, whenprovided at a dosage of 1.00%.

Inhibition of Methylesterification Reactions

For example, ability of the presently disclosed compounds to inhibitmethylesterification reactions by ICMT may be assessed, for example,using assays that measure the reduction of methylated acetyl farnesylcysteine, an ICMT substrate as described for example in Example 87 ofU.S. Published Application No. 2016/0361283. In certain embodiments, thepresently disclosed compounds are considered inhibitors of ICMT whenthey show a percent reduction of methylated acetyl-farnesyl-cysteine, asICMT substrate of at least about 30, 35, 40, 50, 60, 70, 75, 80, 85, 90,95 or 100%, for example when provided at a concentration of 25 μM.

Inhibition of Oxidative Burst

For example, ability of the presently disclosed compounds to inhibitoxidative burst from neutrophils may be assessed, for example, usingassays that measure the reduction of superoxide formation, as describedfor example in Example 88 of U.S. Published Application No.2016/0361283. In certain embodiments, the presently disclosed compoundsare considered inhibitors of oxidative burst from neutrophils when theyshow a percent reduction of superoxide formation of at least about 30,35, 40, 50, 60, 70, 75, 80, 85, 90, 95 or 100%, for example whenprovided at a concentration of 25 μM.

2. Methods of Syntheses

The present invention provides methods of preparing compounds providedherein. As will be appreciated by one of skill in the art, the syntheticmethods described herein may be modified without departing from thescope of the present invention. For example, different startingmaterials and/or different reagents may be used in the inventivesynthetic methods.

Generally, presently provided compounds (e.g., Compounds B, D, F, H andI) can be prepared starting with an appropriately lipidated cysteine(preferably with phytyl or farnesyl moieties) to be added to a solutionof the corresponding activated acid (e.g., with HATU[1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate] or DCC [N,N′-Dicyclohexylcarbodiimide]) inthe presence of an organic base (e.g., trimethylamine or Hünig's base[N,N-Diisopropylethylamine]) to form an amide bond in the end compound.After isolation, these end compounds can be further purified by crashingtheir sodium salts from alcoholic solution with sodium hydroxide orsodium ethoxide. Overall yield after filtration and drying in vacuum forthese end compounds can be, in certain embodiments, in the 30-84% range.

The above method, however, does not produce satisfactory yields for somecompounds of the present invention, particularly compounds C, E, G andI. The appropriately lipidated cysteine (preferably with phytyl orfarnesyl moieties) did not produce any synthetically useful yields ofthe end compounds when treated with CDI, triphosgene or phosgene undermultiple conditions following introduction of the correspondingsecondary amines Surprisingly, the appropriately lipidated cysteinemethyl ester (preferably with phytyl or farnesyl moieties) when treatedwith CDI in organic solvent (preferably DMF, THF or similar polaritysolvent), following by introduction of the corresponding secondary amineand base (preferably trimethylamine or Hünig's base[N,N-Diisopropylethylamine] or inorganic base like Na₂CO₃) and gentleheating to 50° C. formed the desired urea moiety in the title compoundsin good to excellent yields. After isolation, these compounds werefurther purified by crashing their sodium salts from alcoholic solutionwith sodium hydroxide or sodium ethoxide. Overall yield after filtrationand drying in vacuum for these compounds prepared in this alternativemanner can be in 30-84% range.

3. Compositions and Formulations

The present invention provides compositions comprising compounds aspresently described herein. In some embodiments, provided compositionscontain additional components. In some embodiments, all such additionalcomponents are pharmaceutically acceptable and provided compositions arepharmaceutical compositions suitable for administration to a human orother animal. In some embodiments, all such additional components arecosmetically acceptable and provided compositions are cosmeticcompositions. In some embodiments, all such additional components arecosmoceutically acceptable and provided compositions are cosmeceuticalcompositions.

In general, one or more compounds of the present invention may beformulated into pharmaceutical compositions that include at least oneprovided compound of the present invention together with one or morepharmaceutically acceptable carriers, including excipients, such asdiluents, binders and the like, and additives, such as stabilizingagents, preservatives, solubilizing agents, and buffers, as desired.Formulation excipients may include polyvinylpyrrolidone, gelatin,hydroxy cellulose, acacia, polyethylene glycol, manniton, sodiumchloride and sodium citrate. In some embodiments, inventive compositionscontain a pharmaceutically acceptable carrier. In some embodiments, thecompositions of the present invention include a cosmetically acceptablecarrier. In some embodiments, the compositions of the present inventioninclude a cosmeceutically acceptable carrier.

A carrier in certain compositions according to the present invention mayinclude liquid and, in particular may comprise a buffered, isotonic,aqueous solution.

A carrier, including a pharmaceutically acceptable carrier, may be, orinclude, an excipient, such as a diluent, binder (e.g., binding agent)and the like, and or an additive, such as a stabilizing agent,preservative, solubilizing agent, and/or buffer as hereafter described.Pharmaceutical carriers include, without limitation, a binding agent(e.g., hydroxypropyl methylcellulose, polyvinylpyrrolidone, orpregelatinised maize starch, etc.); a filler (e.g., calcium hydrogenphosphate calcium sulfate, ethyl cellulose, gelatin, lactose and othersugars, microcrystalline cellulose, pectin, polyacrylates, etc.); adisintegrant (e.g., glycolate, sodium starch, starch, etc.); a lubricant(e.g., colloidal silicon dioxide, corn starch, hydrogenated vegetableoils, polyethylene glycols, magnesium stearate, metallic stearates,silica, sodium benzoate, sodium acetate, stearic acid, talc, etc.); or awetting agent (e.g., sodium lauryl sulphate, etc.). Additionalpharmaceutically acceptable carriers include, for example, petroleumjelly (Vaseline®), and petroleum.

Additional suitable carriers for the compositions of the presentinvention include, but are not limited to, alcohols, amyloses, animaloil, anti-irritants, chelating agents, colorants, deodorant agents,emulsifiers, fragrances, gelatins, hair conditioning agents,hydroxymethylcelluloses, magnesium stearates moisturizing agents (e.g.,humectants), microcrystalline, mineral oil, natural polymers (e.g.,collagen, gum arabic, polyols, and xanthanes, and the like), organic,ozocerite wax, and inorganic waxes, paraffin, penetration enhancers, pHadjusting agents, preservatives, propellants, salt solutions, silicicacids, surfactants talcs, solubilizing agents, thickeners, viscousparaffins, and water, and combinations thereof. In some embodiments, thepresently disclosed compounds act as acceptable carrier(s) and/orexcipient(s). In certain embodiments, AFC acts as an acceptable carrierand/or excipient, and may be included in compositions containing thepresently disclosed compounds. In some embodiments, it may be desirableto use the carriers in cosmetic compositions, as described in the CTFAInternational Cosmetic Ingredient Dictionary and Handbook, 8th edition,edited by Wenninger and Canterbery, (The Cosmetic, Toiletry, andFragrance Association, Inc., Washington, D.C., 2000), which is hereinincorporated by reference. Also included are the carriers describedhereinabove.

In some embodiments, pharmaceutically acceptable carriers of thecomposition include a sustained release or delayed release carrier. Suchcarriers can be any material capable of sustained or delayed release ofpresently disclosed compounds to provide a more efficient administrationresulting in less frequent and/or decreased dosage of the presentlydisclosed compounds, ease of handling, and extended or delayed effectson diseases, disorders, conditions, syndromes, and the like, beingtreated, prevented or promoted. Non-limiting examples of such carriersinclude liposomes, microsponges, microspheres, or microcapsules ofnatural and synthetic polymers and the like. Liposomes which may enhancethe localized delivery of the compounds of the inventive compositionwithin skin layers, may be formed from a variety of phospholipids, suchas cholesterol, stearylamines or phosphatidylcholines.

For injection or other liquid administration formulations, watercontaining at least one or more buffering constituents is commonlyutilized, and stabilizing agents, preservatives and solubilizing agentsmay also be employed. In some embodiments, a provided pharmaceuticalcomposition is or comprises an isotonic solution.

For solid administration formulations, any of a variety of thickening,filler, bulking and carrier additives may be employed, such as starches,sugars, fatty acids and the like. Topical compositions of the presentinvention can be applied locally to the skin or mucosa and may be in anyform including solutions, oils, creams, ointments, gels, lotions,shampoos, milks, cleansers, moisturizers, sprays, skin patches and thelike.

For most pharmaceutical formulations, non-active ingredients willconstitute the greater part, by weight or volume, of the preparation.For pharmaceutical formulations, it is also contemplated that any of avariety of measured-release, slow-release or time-release formulationsand additives may be employed, so that the dosage may be formulated soas to effect delivery of a provided compound over a period of time. Forexample, gelatin, sodium carboxymethylcellulose and/or other cellulosicexcipients may be included to provide time-release or slower-releaseformulations, especially for administration by subcutaneous andintramuscular injection.

In certain embodiments use, the presently disclosed compounds can becombined as the active ingredient in an admixture with a pharmaceuticalcarrier according to conventional pharmaceutical compounding techniques.Pharmaceutical compositions for the present invention may be formulatedfor delivery by any of a variety of routes including, for example, oral,parenteral (including intravenous), urethral, vaginal, nasal, topical(e.g., dermal, transdermal), pulmonary, deep lung, inhalation, buccal,sublingual routes, or the like.

In preparing compositions containing the presently disclosed compoundsfor cutaneous administration, such as topical (i.e., local), suchcompositions can include pharmaceutical carriers (e.g., sterile andnon-sterile aqueous solutions, non-aqueous solutions in common solventssuch as alcohols, or solutions of presently disclosed compounds inliquid or solid oil bases). Such pharmaceutical carrier solutions alsocan contain buffers, diluents and other suitable additives.

Representative compositions suitable for oral use include, for example,mouthwash, rinse, oral spray, suspension, dental gel, and the like.Typical oral carriers known in the art may be used in the presentinvention. In certain embodiments, the pharmaceutical and/or cosmeticcarriers include water, ethanol, or water-ethanol mixtures.Water-ethanol mixtures can be employed in a weight ratio, for example,from about 1:1 to about 20:1, preferably from about 3:1 to about 20:1,and most preferably from about 3:1 to about 10:1, respectively. The pHvalue of the oral vehicle is generally from about 4 to about 7, andpreferably from about 5 to about 6.5. An oral topical vehicle having apH value below about 4 is generally irritating to the oral cavity and anoral vehicle having a pH value greater than about 7 generally results inan unpleasant mouth feel.

Oral topical inventive compositions may also contain conventionaladditives normally employed in those products. Conventional additives asdescribed herein include a coloring agents, emulsifiers, fluorineproviding compounds, humectants, sweetening agents, and pH adjustingagents, provided that such additives do not interfere with thetherapeutic, cosmetically, or cosmeceutically beneficial properties ofinventive compositions. Additional ingredients that may be used incompositions of the present invention include fluorine providingcompounds, additional active ingredients, new excipients, protectives,and demulcents, as described herein.

Fluorine providing compounds may be fully or slightly water soluble andare characterized by their ability to release fluoride ions or fluoridecontaining ions in water and by their lack of reaction with othercomponents in the composition. Typical fluorine providing compoundsinclude alkali metal fluorides, inorganic fluoride salts such aswater-soluble alkali metal, alkaline earth metal, heavy metal salts, forexample, aluminum mono- and di-fluorophosphates, ammonium fluoride,ammonium fluorosilicate, barium fluoride, cuprous fluoride, fluorinatedsodium calcium pyrophosphate, potassium fluoride, sodium fluoride,sodium fluorosilicate, sodium fluorozirconate, sodiummonofluorophosphate, stannic fluoride, stannous fluoride and zincfluoride, monofluorophosphates, such as sodium and stannous fluoride,sodium monofluorophosphate, tin fluoride and combinations thereof.

Amounts of fluorine providing compounds present in oral, topicalinventive compositions provided herein depend upon the type of fluorineproviding compound employed, solubility of the fluorine compound, andthe nature of the final oral inventive composition. Amount of fluorineproviding compounds used must be a nontoxic amount. In general, fluorineproviding compounds when used will be present in an amount up to about1%, from about 0.001% to about 0.1%, and rom about 0.001% to about0.05%, by weight of oral topical inventive compositions provided herein.

Typical sweetening agents (sweeteners) that are well known in the artinclude those that are both natural and artificial sweeteners, may beemployed. Sweetening agent used may be selected from a wide range ofmaterials including water-soluble sweetening agents, water-solubleartificial sweetening agents, water-soluble sweetening agents derivedfrom naturally occurring water-soluble sweetening agents, dipeptidebased sweetening agents, and protein based sweetening agents, includingmixtures thereof.

In some embodiments, compositions of the present invention can furtherinclude one or more additional (“compatible”, as defined herein) activeingredients which are aimed at providing compositions with anotherpharmaceutical, cosmetic, or cosmeceutical effect, in addition to thatprovided by the presently disclosed compound of inventive compositionsprovided herein.

Additional active ingredients according to the present inventioninclude, without limitation, one or more, in any combination, of aprotective agent, an emollient, an astringent, an irritant, akeratolytic, a sun screening agent, a sun tanning agent, an antibioticagent, an antifungal agent, an antiviral agent, an antiprotozoal agent,an anesthetic agent, a steroidal anti-inflammatory agent, anon-steroidal anti-inflammatory agent, an antipruritic agent, ananti-oxidant agent, a chemotherapeutic agent, an anti-histamine agent, avitamin, a hormone, an anti-dandruff agent, an anti-wrinkle agent, ananti-skin atrophy agent, a sclerosing agent, a cleansing agent, acaustic agent and a hypo-pigmenting agent.

Compositions according to the present invention, which further includeone or more additional active ingredients, can therefore be furtherefficiently used, in addition to their use as a treatment for anepithelial-related condition, in the treatment of any medical, cosmeticand/or cosmeceutical condition in which applying the additional activeingredient is beneficial.

Protectives as described herein may take the form of dusting powders,adsorbents, mechanical protective agents, and plasters. Dusting powdersare relatively inert and insoluble materials that are used to cover andprotect epithelial surfaces, ulcers and wounds. Usually, thesesubstances are finely subdivided powders that absorb moisture and canact as a dessicant. The absorption of skin moisture decreases frictionand also discourages certain bacterial growth. Some of the materialsused as protective adsorbents include bentonite, insoluble salts ofbismuth, boric acid, calcium carbonate, (precipitated), cellulose, cornstarch, magnesium stearate, talc, titanium dioxide, zinc oxide, and zincstearate.

In some embodiments, protectives also can be administered to the skin toform an adherent, continuous film that may be flexible or semi-rigiddepending on the materials and the formulations as well as the manner inwhich they are applied. This material may serve several purposesincluding providing occlusion from the external environment, providingchemical support, and serving as vehicles for other medicaments.

In some embodiments, protectives included in compositions of the presentinvention are demulcents. Demulcents often are applied to the surface ina viscid, sticky preparation that covers the area readily and may bemedicated. A number of chemical substances possess demulcent properties.

In practical use, provided compounds herein can be combined as an activeingredient in an admixture with a pharmaceutical carrier according toconventional pharmaceutical compounding techniques. The carrier may takea wide variety of forms depending on the form of preparation desired foradministration, for example, oral, parenteral (including intravenous),urethral, vaginal, nasal, dermal, transdermal, pulmonary, deep lung,inhalation, buccal, sublingual, or the like.

In preparing the compositions for oral dosage form, any of the usualpharmaceutical media may be employed, such as, for example, water,glycols, oils, alcohols, flavoring agents, preservatives, coloringagents and the like in the case of oral liquid preparations, such as,for example, suspensions, elixirs and solutions; or carriers such asstarches, sugars, microcrystalline cellulose, diluents, granulatingagents, lubricants, binders, disintegrating agents and the like in thecase of oral solid preparations such as, for example, powders, hard andsoft capsules and tablets.

In some embodiments, one or more of the presently disclosed compounds,carrier and, optionally, additional active ingredients are formed into acomposition in the form of a solution, emulsion or gel suspension, aswill be further described herein.

In some embodiments, a presently disclosed compound, a pharmaceutical orcosmetic carrier and, optionally, one or more additional activeingredients, are in the form of a solution. A solution can be preparedby mixing a solute or dissolved substance (such as a compound of theinvention and, optionally, one or more active ingredient(s)) uniformlythroughout a solvent carrier such as water or organic solvents, such asthe alcohols (e.g. ethanol or isopropanol, acetone).

In some embodiments, the solution is an aqueous solution wherein aprovided compound may be appropriately buffered by means of saline,acetate, phosphate, citrate, acetate or other buffering agents, whichmay be at any physiologically acceptable pH, generally from about pH 4to about pH 7. Combinations of buffering agents may also be employed,such as phosphate buffered saline, a saline and acetate buffer, and thelike. In the case of saline, a 0.9% saline solution may be employed. Inthe case of acetate, phosphate, citrate, acetate and the like, a 50 mMsolution may be employed. In addition to buffering agents, suitablepreservatives may be employed, to prevent or limit bacteria and othermicrobial growth. One such preservative that may be employed is 0.05%benzalkonium chloride.

In some embodiments, inventive compositions comprising a presentlydisclosed compound, a carrier and other, optional, ingredients areprovided in the form of an emulsion. Emulsions are a two-phase systemprepared by combining two immiscible liquid carriers, one of which isdisbursed uniformly throughout the other and consists of globules thathave diameters equal to or greater than those of the largest colloidalparticles. The globule size is critical and must be such that the systemachieves maximum stability. Usually, separation of two phases will notoccur unless a third substance, an emulsifying agent, is incorporated.Thus, a basic emulsion in the context of the present invention typicallycontains two or more components (e.g., two immiscible liquid carriers,an emulsifying agent, and a presently disclosed compound(s)). In someembodiments, a presently disclosed compound can itself be an emulsifyingagent, or compositions containing a presently disclosed compound caninclude an emulsifying agent. Typically, emulsions incorporate anaqueous phase into a non-aqueous phase (or vice versa). However, it ispossible to prepare emulsions that are largely non-aqueous, for example,anionic and cationic surfactants of the non-aqueous immiscible systemglycerin and olive oil. Exemplary emulsifying agents are describedherein.

In some embodiments, inventive compositions including a presentlydisclosed compound, are provided in the form of gel suspensions, (asemi-solid carrier) or solid carrier to form a paste, powder, ointment,cream, lotion, hydrogel or the like. Exemplary ointments that may beprepared as a gel-suspension include semi-solid preparations intendedfor external application to the epithelium. Generally, ointment basesare categorized into hydrocarbon bases (oleaginous), which may use whitepetroleum as a base; adsorption bases (anhydrous), which might usehydrophilic petroleum or anhydrous lanolin; emulsion bases (water andoil type); emulsion bases (oil and water type); and water soluble bases,which often use polyethylene glycol as an ointment base.

Additional compositions of the present invention can be readily preparedusing technology known in the art as described in Remington'sPharmaceutical Sciences, 18^(th) or 19^(th) editions, published by theMack Publishing Company of Easton, Pa.

In some embodiments, inventive compositions formulated as aqueoussuspensions wherein a presently disclosed compound is in admixture withexcipients additives and/or suitable for the manufacture of aqueoussuspensions. Such additives and/or excipients are suspending agents, forexample, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gumtragacanth, and gum acacia; dispersing or wetting agents may be anaturally occurring phosphatide such as lecithin, or condensationproducts of an alkylene oxide with fatty acids, for example,polyoxyethylene stearate, or condensation products of ethylene oxidewith long chain aliphatic alcohols, for example, heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partialesters derived from fatty acids and a hexitol such as polyoxyethylenesorbitol monooleate, or condensation products of ethylene oxide withpartial esters derived from fatty acids and hexitol anhydrides, forexample polyethylene sorbitan monooleate. Aqueous suspensions also maycontain one or more coloring agents, one or more flavoring agents, andone or more sweetening agents, such as sucrose or saccharin.

In some embodiments, inventive compositions formulated as oilysuspensions by suspending a provided compound in a vegetable oil (e.g.,arachis oil, olive oil, sesame oil, coconut oil, or a mineral oil, suchas liquid paraffin). Oily suspensions may contain a thickening agent(e.g., beeswax, hard paraffin or cetyl alcohol). Sweetening agents, suchas those described herein, and flavoring agents may be added to providea palatable oral composition. Such compositions may be preserved by theaddition of an antioxidant (e.g., ascorbic acid).

In some embodiments, inventive compositions formulated as dispersiblepowders and/or granules are suitable for compositions of an aqueoussuspension by adding water. A presently disclosed compound in suchpowders and granules can be provided in admixture with a dispersing orwetting agent, suspending agent, and one or more preservatives. Suitabledispersing or wetting agents and suspending agents are exemplified bythose already mentioned herein. Additional excipients, for example,sweetening, flavoring and coloring agents also may be incorporated.

Compositions of the invention also may be in the form of oil in wateremulsions. The oily phase may be a vegetable oil, for example, olive oilor arachis oil, or a mineral oil, for example a liquid paraffin, or amixture thereof. Suitable emulsifying agents may be naturally occurringgums, for example, gum acacia or gum tragacanth, naturally-occurringphosphatides, for example soy bean, lecithin, and esters or partialesters derived from fatty acids and hexitol anhydrides, for examplesorbitan monooleate, and condensation products of the partial esterswith ethylene oxide, for example, polyoxyethylene sorbitan monooleate.The emulsions also may contain sweetening and flavoring agents.

Besides oral and topical compositions, compositions containing thepresently disclosed compounds can also be provided, for example, forparenteral and pulmonary administration, as disclosed in U.S. PublishedApplication No. 2016/0361283, which is hereby incorporated by reference.

4. Administration and Dosage Forms

The presently disclosed compounds of the invention may be formulated byany means known in the art, including but not limited to formulation astablets, capsules, caplets, suspensions, powders, lyophilizedpreparations, suppositories, ocular drops, skin patches, oral solubleformulations, sprays, aerosols and the like, and may be mixed andformulated with buffers, binders, excipients, stabilizers, anti-oxidantsand other agents known in the art. In general, any route ofadministration by which provided compounds of the invention areintroduced across an epidermal layer of cells may be employed.Administration means may thus include administration through mucousmembranes, buccal administration, oral administration, dermaladministration, inhalation administration, pulmonary administration,nasal administration, urethral administration, vaginal administration,and the like.

In general, compositions comprising a therapeutically orpharmaceutically effective amount of an inventive composition includinga presently disclosed compound may be formulated for administration inunit dosage forms.

Oral Administration

Because of their ease of administration, tablets and capsules representan advantageous oral unit dosage form. If desired, a compositionincluding a presently disclosed compound may be coated by standardaqueous or nonaqueous techniques. The amount of active compound, i.e. apresently disclosed compound of the present invention, in suchtherapeutically useful compositions is such that an effective dosagewill be obtained. In another advantageous dosage unit form, sublingualpharmaceutical compositions may be employed, such as sheets, wafers,tablets or the like. Compositions of the present invention may be inadditional forms suitable for oral use, for example, troches, lozenges,pills, aqueous or oily suspensions, solutions, dispersible powders orgranules, emulsions, hard or soft capsules, syrups or elixirs, pastes,gels or the like.

Topical Administration

Formulations of the present invention suitable for topical applicationto the skin can take the form of an ointment, cream, lotion, paste, gel,spray, aerosol, or oil. Additives which may be used include vaseline,lanoline, polyethylene glycols, alcohols, transdermal enhancers, andcombinations of two or more thereof.

In some embodiments, formulations suitable for topical applicationachieve transdermal delivery. Transdermal pharmaceutical devices includepatches, occlusive dressings, occlusive formulations, hypodermic sprays,iontophoretic systems, gels and infusion pumps, all of which are wellknown in the art. A transdermal patch which includes a pharmaceuticalmay generally include a backing layer impermeable to the pharmaceutical,a reservoir to house the pharmaceutical, and an adhesive cover to beremoved upon use of the patch and for adhesion to the skin of a patient.

Formulations suitable for transdermal administration may also bepresented as medicated bandages or discrete patches adapted to remain inintimate contact with the epidermis of the recipient for a prolongedperiod of time. Representative examples of suitable transdermal patchesinclude, for example, those developed by NeuroDerm Ltd. (Israel) and/orthat used to deliver estradiol, for example, those developed by NovogynePharmaceuticals. Formulations suitable for transdermal administrationmay also be delivered by iontophoresis (passage of a small electriccurrent (^(˜)15 mA) to “inject” electrically charged ions into the skin)through the skin. For this, the dosage form typically takes the form ofan optionally buffered aqueous solution of the active compound, i.e. apresently disclosed compound.

Formulations suitable for transdermal administration may also bedelivered by using an infusion pump connected to a needle that isinserted through the skin, for example, those developed by Medtronicused to deliver insulin. Amounts of compound used in a transdermaldevice as described herein may vary, depending on many factors includingthe size of the device and its release characteristics, the amount ofthe pharmaceutical active agent and the estimated duration of action ofthe device. Broadly, amounts of a presently disclosed compound typicallyrange from about 0.1% to about 10% w/v.

5. Dosage: Therapeutically Effective Amount

The actual quantity of the presently disclosed compounds administered toa patient will vary depending on the severity and type of indication,the mode of administration, the particular compound used, theformulation used, and the response desired.

The dosage for treatment is administration, by any of the foregoingmeans or any other means known in the art, of an amount sufficient tobring about the desired therapeutic effect. Thus, a therapeuticallyeffective amount may be an amount of a presently disclosed compound orpharmaceutical composition that is sufficient to induce a desiredeffect, including but not limited to an anti-inflammation effect. Thoseof ordinary skill in the art will appreciate that a therapeuticallyeffective amount may be administered by means of a single dose ormultiple doses, and that compositions provided herein may contain a unitdose of a therapeutically effective amount.

In general, the presently disclosed compounds are highly active. Forexample, a presently disclosed compound may be administered from about0.001 mg/kg to about 100 mg/kg, from about 0.01 mg/kg to about 50 mg/kg,from about 0.1 mg/kg to about 40 mg/kg, from about 0.5 mg/kg to about 30mg/kg, from about 0.01 mg/kg to about 10 mg/kg, from about 0.1 mg/kg toabout 10 mg/kg, or from about 1 mg/kg to about 25 mg/kg of a presentlydisclosed compound per subject body weight per day to obtain a desiredtherapeutic effect. A desired dosage may be delivered to a subject onlyonce. A desired dosage may be delivered more than three times per day,three times per day, two times per day, once per day, every other day,every third day, every week, every two weeks, every three weeks, everyfour weeks, every two months, every six months, every twelve months,every two years, every three years, every four years, every five years,every 10 years, or every 20 years. In certain embodiments, the desireddosage may be delivered using multiple administrations (e.g., two,three, four, five, six, seven, eight, nine, ten, eleven, twelve,thirteen, fourteen, fifteen, or more administrations). The skilledartisan will appreciate that certain factors can influence the dosageand timing required to effectively treat a subject, including but notlimited to the specific compound selected, the desired therapeuticresponse, the route of administration, the formulation, the severity ofthe disease or disorder, previous treatments, the general health and/orage of the subject, other diseases present, and/or other factors knownto those of skill in the art.

6. Uses

In certain embodiments, the present invention provides novel compounds,which might themselves be added to or combined with otherpharmaceutically active agents, compositions comprising at least onepresently disclosed compound or combination with other pharmaceuticallyactive agents thereof, and/or methods of their preparation or use in theamelioration, treatment or prevention of, for example, certainconditions, diseases or disorders associated with inflammation or thesuppression of inflammatory responses.

In certain particular embodiments, the present invention providesanti-inflammatory compounds and compositions described here that inhibitinflammation and are therefore useful in the treatment of diseases,conditions or disorders associated with inflammation.

In certain embodiments, the present invention provides novel compoundsand compositions that modulate inflammation. Although not wishing to bebound by one theory, it is believed that compounds and compositionsdescribed herein modulate levels of inflammatory mediators, for example,cytokines. Non-limiting examples of inflammatory mediators modulated byprovided compounds and compositions include but are not limited toIL-la, IL-113, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10,IL-11, IL-12/IL-23 p40, IL13, IL-17, IL-18, TGF-β, IFN-γ, GM-CSF, Groα,MCP-1 and TNF-α. Although not wishing to be bound by one theory, it isbelieved that compounds and compositions described herein modulatelevels of inflammatory mediators that are associated with a variety ofsignal transduction pathways. Non-limiting examples of signaltransduction pathways that result in release of inflammatory mediatorssuch as cytokines, include but are not limited to G-protein-mediated,PPAR-mediated, Toll-like receptor-mediated, and TNF-α receptor-mediated.Although not wishing to be bound by one theory, it is believed that thepresently disclosed compounds modulate T-helper cell infiltration andaccumulation. Although not wishing to be bound by one theory, it isbelieved that the presently disclosed compounds and compositions inhibitoxidative burst from neutrophils and are therefore anti-oxidants.

In certain embodiments, the present invention provides novel compoundsand compositions that relate to treating or lessening the severity ofone or more diseases in which protein inhibitors that modulate theG-protein signaling cascade are known to play a role. Although notwishing to be bound by one theory, it is believed that the presentlydisclosed compounds inhibit methylesterifcation reactions by a specificmembrane associated S-adenosylmethionine-dependent isoprenyl-S-isoprenylmethyltransferase (“ICMT”) resulting in carboxy-terminal polyisoprenoidcysteine modifications of a number of key factors in G-protein signalingpathway. In certain embodiments, the presently disclosed compounds alterthe interactions among polyisoprenylated signal transduction proteins,such as G-proteins and the protein regulatory targets with which theyinteract, or other intracellular signaling proteins.

In certain embodiments, the presently disclosed compounds areadministered in vitro. In certain embodiments, such compounds areadministered in vivo.

Another aspect of the present invention is directed to methods oftreating, preventing, or ameliorating inflammation by administering aneffective amount of a presently disclosed compound.

In some embodiments, one or more inventive compounds, alone or togetherwith one or more other pharmaceutically active agents, is used to whitenskin. In some such embodiments, a presently disclosed compound isapplied topically to whiten skin.

In general, the actual quantity of provided compounds of the presentinvention administered to a patient will vary depending on the severityand type of indication, the mode of administration, the particularcompound used, the formulation used, and the response desired.

The dosage for treatment is administration, by any of the foregoingmeans or any other means known in the art, of an amount sufficient tobring about the desired therapeutic effect. Thus, an effective amountincludes an amount of a presently disclosed compound (or a mixture ofpresently disclosed compounds) that is sufficient to induce a desiredeffect, including specifically, for example, an anti-inflammation effector a proinflammatory effect depending on the diseases, disorders,conditions, syndromes, and the like, being treated, prevented orpromoted.

Methods (A) Anti-Inflammatory

Specifically, the present invention relates to a method of treating orlessening the severity of inflammatory diseases or disorders selectedfrom inflammation (acute or chronic), inflammatory diseases or disorders(e.g., asthma, autoimmune diseases, and COPD including emphysema,chronic bronchitis and small airways disease, etc.), inflammatoryresponses of the immune system, skin diseases (e.g., reducing acute skinirritation for patients suffering from rosacea, atopic dermatitis,seborrheic dermatitis, psoriasis), irritable bowel syndrome (e.g.,Crohn's disease and ulcerative colitis, etc.), NeurodegenerativeDisorders (Parkinson's disease, Alzheimer's disease, Huntington'sdisease, Dementia pugilistica, Pick's disease, Guam parkinsonismdementia complex, Fronto-temporal dementia, Cortico-basal degeneration,Pallido-pontal-nigral degeneration, Progressive supranuclear palsy,Dementia with Lewy bodies (DLB), and multiple system atrophy (MSA)), aswell as inflammation associated with spinal cord injury to promote nerveregeneration and inhibition of rejection of genetically engineered cellsby the immune system during in vivo gene therapy, wherein the methodcomprises administering to a patient in need thereof a composition ofthe present invention that includes one or more of the presentlydisclosed compounds.

In some embodiments, the presently disclosed compounds of the presentinvention are capable of effectively inhibiting inflammatory responses.Thus, the presently disclosed compounds are inhibitors of edema,erythema and myeloperoxidase and are therefore useful for treating oneor more disorders associated with inflammatory diseases or disorders asdescribed herein.

In some embodiments, the provided anti-inflammatory compounds of thepresent invention are capable of effectively inhibiting inflammatoryresponses by decreasing the levels or production of inflammatorymediators such as inflammatory cytokines, for example IL-1α, IL-1β,IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11,IL-12/IL-23 p40, IL13, IL-17, IL-18, TGF-β, IFN-γ, GM-CSF, Groα, MCP-1and TNF-α. Thus, the presently disclosed compounds are inhibitors ofproinflammatory cytokines and are therefore useful in treating one ormore disorders associated with inflammatory diseases, conditions ordisorders described herein. Therefore, the presently disclosed compoundsare administered to a subject suffering from or susceptible to one ormore inflammatory diseases, conditions or diseases.

In some embodiments, the treatment of inflammatory diseases or disordersis achieved using the presently disclosed compounds without having theside effects of corticosteroids or NSAIDS.

In some embodiments, the presently disclosed compounds of the presentinvention are capable of effective inhibiting oxidative burst responsefrom neutrophils. Thus, the presently disclosed compounds are inhibitorsof oxidative burst response and are therefore useful in the treatment oramelioration of symptoms relating to oxidative damage caused by chemicalor environmental factor (e.g., UV damage on the skin). Therefore, thepresently disclosed compounds are administered to a subject sufferingfrom conditions associated with oxidative damage. In some embodiments,combinations of such sun screening agents with one or more presentlydisclosed compounds provided herein exhibit anti-oxidant effects (e.g.,inhibition of superoxide formation).

(B) Skin Conditions

In some embodiments, provided herein is a method for treating orpreventing a skin condition, the method comprising the step of topicallyapplying onto a surface of a subject, including a human, in needthereof, an effective amount of a composition comprising at least onepresently disclosed compound, a carrier and optionally an additionalactive ingredient. In one particular embodiment, provided herein is amethod for treating or preventing a skin condition, the methodcomprising the step of topically applying onto a surface of a subject,including a human, in need thereof, at least, for example, 0.1 mg of apresently disclosed compound. In a further embodiment, provided hereinis a method of promoting healthy skin in a subject, including a human,in need thereof, the method comprising the step of topically applyingonto a surface of a subject, including a human, in need thereof, aneffective amount of a composition comprising at least one presentlydisclosed compound, a carrier and optionally an additional activeingredient. In a further embodiment, provided herein is a method ofpromoting healthy skin in a subject, including a human, in need thereof,the method comprising the step of topically applying onto a surface of asubject, including a human, in need thereof, at least 0.1 mg of apresently disclosed compound.

In a further embodiment, the present invention provides a method fortreating or preventing inflammation in a subject, including a human, inneed thereof, comprising the step of administering an effective amountof a composition comprising at least one presently disclosed compound, acarrier and optionally an additional active ingredient. In a furtheraspect, the present invention provides a method for treating orpreventing inflammation in a subject, including a human, in needthereof, comprising the step of administering at least 0.1 mg of apresently disclosed compound.

In certain embodiments, the present invention provides uses of apresently disclosed compound in the treatment or prevention of diseasesor conditions associated with suppression of inflammatory responses. Incertain embodiments, the present invention provides a composition fortreating or preventing conditions associated with suppression of theinflammatory responses, in a subject, including a human, in need oftreatment thereof, that comprises of at least one a presently disclosedcompound, a carrier and optionally, an additional active ingredient. Ina further embodiment, provided herein is a method for treating orpreventing a disease or condition associated with suppression ofinflammatory responses, in a subject, including a human, in needthereof, the method comprising the step of administering an effectiveamount of a composition comprising at least one presently disclosedcompound, a carrier and optionally an additional active ingredient. In afurther aspect, provided herein is a method for treating or preventing adisease or condition associated with suppression of inflammatoryresponses, in a subject, including a human, in need thereof, the methodcomprising the step of administering at least 0.1 mg of a presentlydisclosed compound.

Exemplary diseases, disorders or conditions (e.g., rosacea, psoriasis,atopic dermatitis and seborrhic dermatitis) that may be treated with apresently disclosed compound, in accordance with the present inventionare addressed individually below.

Rosacea

Rosacea is a chronic, inflammatory skin disorder that afflicts about 14million people in the US (FoxAnalytics, The Dermatology Market Outlookto 2011, B.I. LTD, Editor: London, UK, p. 201; Crandall, M. A. MarketIntelligence Report, K. Information, Editor, 2008: New York. p 359).With peak onset between the ages of 51 and 60, its incidence will growsubstantially in the years ahead. The condition is characterized by aconstellation of symptoms that include central facial erythema,telangiectasias, papules, granulomatous nodules, phyma formation andocular changes. Flares and remissions occur without rationale. There areno known cures for rosacea. Exemplary cytokines associated with rosaceamay include TNFα, ILβ, IL-6, IL-8, MCP-1 and Groα.

Psoriasis

Psoriasis is a chronic inflammatory skin disease affecting about 125million people worldwide and approximately 2-3% of the generalpopulation in the US and Europe (Crandall, M. A. Market IntelligenceReport, K. Information, Editor, 2008: New York. P. 359; Naldi, L., Curr.Drug Targets Inflamm. Allergy, 2004, 3: 121-128). Although thepathogenesis of psoriasis has not been fully elucidated, recent advancesdemonstrate targeting key mediators of inflammation as a promisingtherapeutic approach (Numerof et al., BioDrugs, 2006, 20: 93-103; Menteret al., J. Am. Acad. Dermatol., 2009, 60: 643-659). Direct therapeuticapproaches include using antibodies or soluble receptors (i.e.,biologics) to directly neutralize the specific cytokine of interest.However, biologic cytokine-derived therapies are expensive to produce,require sustained high blood levels in order to develop significant skinlevels, may induce the production of neutralizing antibodies (leading toa diminished response to therapy), and must be administered byinjection. Topical treatments have largely been ineffective, so marketgrowth has been driven by systemic agents that have serious potentialside effects. Corticosteroids remain the cornerstone of current topicaltreatment, but they are far from ideal. Long-term steroid use bringssafety concerns ranging from issues of systemic absorption to cutaneousatrophy and its various clinical presentations. Today's US market forpsoriasis treatments is greatly underserved, as only 60% of sufferersare being treated (Horn et al., J. Am. Acad. Dermatol. 2007, 57:957-962).

Psoriasis can be conceived in simple terms, as a self-reinforcing loop,in which deregulated inflammatory activity stimulates the epidermalStat3c signaling pathway in the epidermis resulting in epidermalhyperplasia. The affected keratinocytes secrete cytokines which simulatethe immune system, including T-helper cell (THc) infiltration andaccumulation. Cytokines from the activated immune cells positivelyfeedback on to the epidermal Stat3c pathway maintaining and amplifyingthe pathophysiology. Inhibition of THc infiltration and accumulationwould decrease Stat3c expression and the onset of psoriasis. Exemplarycytokines associated with psoriasis may include TNFα, IL1α, ILβ, IL-2,IL-6, IL-8, IL-12, IL-17, MCP-1, Groα and IFNγ.

Inflammatory Cytokines and Psoriasis

In some embodiments, the present invention provides methods of treating,ameliorating, controlling, or preventing inflammatory skin conditionssuch as psoriasis comprising administering to a subject in need thereofa dosage form comprising at least about 0.1 mg of a presently disclosedcompound, wherein cytokine levels and/or activity (e.g., TNF-α levelsand/or activity) are reduced by more than about 20% (e.g., as determinedusing a K5.Stat3c psoriasis mouse model).

In some embodiments, the present invention provides methods of treating,ameliorating, controlling, or preventing inflammatory skin conditionssuch as psoriasis comprising administering to a subject in need thereofa dosage form comprising at least about 0.1 mg of a presently disclosedcompound, wherein cytokine levels and/or activity (e.g., IL-α levelsand/or activity) are reduced by more than about 20% (e.g., as determinedusing a K5.Stat3c psoriasis mouse model).

In some embodiments, the present invention provides methods of treating,ameliorating, controlling, or preventing inflammatory skin conditionssuch as psoriasis comprising administering to a subject in need thereofa dosage form comprising at least about 0.1 mg of a presently disclosedcompound, wherein cytokine levels and/or activity (e.g., IL-β levelsand/or activity) are reduced by more than about 20% (e.g., as determinedusing a K5.Stat3c psoriasis mouse model).

In some embodiments, the present invention provides methods of treating,ameliorating, controlling, or preventing inflammatory skin conditionssuch as psoriasis comprising administering to a subject in need thereofa dosage form comprising at least about 0.1 mg of a presently disclosedcompound, wherein cytokine levels and/or activity (e.g., IL-2 levelsand/or activity) are reduced by more than about 20% (e.g., as determinedusing a K5.Stat3c psoriasis mouse model).

In some embodiments, the present invention provides methods of treating,ameliorating, controlling, or preventing inflammatory skin conditionssuch as psoriasis comprising administering to a subject in need thereofa dosage form comprising at least about 0.1 mg of a presently disclosedcompound, wherein cytokine levels and/or activity (e.g., IL-6 levelsand/or activity) are reduced by more than about 20% (e.g., as determinedusing a K5.Stat3c psoriasis mouse model).

In some embodiments, the present invention provides methods of treating,ameliorating, controlling, or preventing inflammatory skin conditionssuch as psoriasis comprising administering to a subject in need thereofa dosage form comprising at least about 0.1 mg of a presently disclosedcompound, wherein cytokine levels and/or activity (e.g., IL-8 levelsand/or activity) are reduced by more than about 20% (e.g., as determinedusing a K5.Stat3c psoriasis mouse model).

In some embodiments, the present invention provides methods of treating,ameliorating, controlling, or preventing inflammatory skin conditionssuch as psoriasis comprising administering to a subject in need thereofa dosage form comprising at least about 0.1 mg of a presently disclosedcompound, wherein cytokine levels and/or activity (e.g., IL-12 levelsand/or activity) are reduced by more than about 20% (e.g., as determinedusing a K5.Stat3c psoriasis mouse model).

In some embodiments, the present invention provides methods of treating,ameliorating, controlling, or preventing inflammatory skin conditionssuch as psoriasis comprising administering to a subject in need thereofa dosage form comprising at least about 0.1 mg of a presently disclosedcompound, wherein cytokine levels and/or activity (e.g., IFN-γ levelsand/or activity) are reduced by more than about 20% (e.g., as determinedusing a K5.Stat3c psoriasis mouse model).

In some embodiments, the present invention provides methods of treating,ameliorating, controlling, or preventing inflammatory skin conditionssuch as psoriasis comprising administering to a subject in need thereofa dosage form comprising at least about 0.1 mg of a presently disclosedcompound, wherein cytokine levels and/or activity (e.g., MCP-1 levelsand/or activity) are reduced by more than about 20% (e.g., as determinedusing a K5.Stat3c psoriasis mouse model).

In some embodiments, the present invention provides methods of treating,ameliorating, controlling, or preventing inflammatory skin conditionssuch as psoriasis comprising administering to a subject in need thereofa dosage form comprising at least about 0.1 mg of a presently disclosedcompound, wherein cytokine levels and/or activity (e.g., Gro-α levelsand/or activity) are reduced by more than about 20% (e.g., as determinedusing a K5.Stat3c psoriasis mouse model).

In some embodiments, the present invention provides methods of treating,ameliorating, controlling, or preventing inflammatory skin conditionssuch as psoriasis comprising administering to a subject in need thereofa dosage form comprising at least about 0.1 mg of a presently disclosedcompound, having an activity in the inhibition of (more than about 20%)of levels of CD3+ T-helper cells, determined using a K5.Stat3c psoriasismouse model.

Atopic Dermatitis

Atopic dermatitis, or eczema, is characterized by chronic inflammationand irritation of the skin. Its causes are varied but immunological innature. In the US, prevalence is 10% to 20% in children and 1% to 3% inadults. Topical dermatitis is caused by exposure to substances such aspoison ivy, detergents and cosmetics that trigger allergic skinreactions. According to present theories, atopic dermatitis is thoughtto be caused by skin barrier defects that lead to increased exposure tosubstances such as allergens exposed by inhalation or ingestion. Whendermatitis occurs, corticosteroids are the primary treatment. Atopicdermatitis, however, disproportionately affects children, and long-termsteroid use in this population raises safety concerns. Exemplarycytokines associated with atopic dermatitis include but are not limitedto TNFα, IL1β, IL-6, IL-8, MCP-1, Groα, IL-4, IL-5, IL-10, IL-13, IL-17and IFNγ.

Histopathology of atopic dermatitis (AD) skin lesions reveals an intensemononuclear cell infiltrate in the dermis with T cells playing acritical role in inducing and maintaining inflammatory cutaneousconditions. While not bound by any particular theory, in the acute stageof AD, the predominant phenotype is a Th2/Th17 immune response, whilechronic AD lesions are primarily Th1. The cytokines produced in theseskewed immune responses are targets for therapeutic intervention.Activation of Toll-like receptor-4 (TLR4) signaling via several ligands(e.g. Ni2+, S. aureus, and LPS) in endothelial cells, keratinocytes andmonocytes also contributes to the developing inflammatory response thatresults in atopic dermatitus. Thus, effectively targeting both TLR andTh1/Th17/Th2 cytokine signaling, which is provided in embodiments of thepresent invention by administering present compounds to a subject,provides a novel therapeutic approach for topically treating atopicdermatitis.

The present compounds (e.g., Compound C) target both TLR cytokinesignaling and Th1/Th17/Th2 cytokine signaling, multiple targets inatopic dermatitis pathogenesis. As discussed in greater detail in theExamples, the presently disclosed compounds (e.g., Compound C) are shownin multiple cell-based assays targeting key pro-inflammatory cytokinesthat drive AD allergic pathogenesis. In human PBMCs, the presentcompounds inhibit IL-4 cytokine release elicited by CD3/CD28 andabrogates a Ni²⁺-TLR4 response in endothelial cells by reducing IL-6. InNHEKs, the present compounds inhibit S. aureus-induced release of TSLP.Activity in vitro is equal to or more potent than topical AD therapies,AN2728, with the possible exception of the inhibition of IL-4 inductionby AN2728. Allergic responses are characterized by early and latephases, possibly representing different inflammatory pathways.

While not being bound by any particular theory, it is believed thatstrong inhibition of IL-6 production will prove particularly effectiveto treat the early inflammatory phase of AD. Utilizing in vivo models,the present compounds (e.g. Compound C) exhibit anti-inflammatoryactivity in the TPA acute inflammation ear model. Moreover, in thedelayed type hypersensitivity (DTH) oxazolone mouse model, whichinvolves both early and late phases, the present compounds are shown tohave higher potency than AN2728, reducing edema and have similar effecton blocking IL-4 production, possibly due to the present compound'sgreater effect on early phase pathways.

Inflammatory Cytokines and Atopic Dermatitis

According to one aspect, the present invention provides methods oftreating, ameliorating, controlling, or preventing inflammatory skinconditions such as atopic dermatitis comprising administering to asubject in need thereof a dosage form comprising at least about 0.1 mgof a presently disclosed compound, wherein cytokine levels and/oractivity (e.g., TNF-α levels and/or activity) are reduced by more thanabout 20% (e.g., as determined using an oxazolone-challenged atopicdermatitis mouse model).

According to one aspect, the present invention provides methods oftreating, ameliorating, controlling, or preventing inflammatory skinconditions such as atopic dermatitis comprising administering to asubject in need thereof a dosage form comprising at least about 0.1 mgof a presently disclosed compound, wherein cytokine levels and/oractivity (e.g., IL-α levels and/or activity) are reduced by more thanabout 20% (e.g., as determined using an oxazolone-challenged atopicdermatitis mouse model).

According to one aspect, the present invention provides methods oftreating, ameliorating, controlling, or preventing inflammatory skinconditions such as atopic dermatitis comprising administering to asubject in need thereof a dosage form comprising at least about 0.1 mgof a presently disclosed compound, wherein cytokine levels and/oractivity (e.g., IL-β levels and/or activity) are reduced by more thanabout 20% (e.g., as determined using an oxazolone-challenged atopicdermatitis mouse model).

According to one aspect, the present invention provides methods oftreating, ameliorating, controlling, or preventing inflammatory skinconditions such as atopic dermatitis comprising administering to asubject in need thereof a dosage form comprising at least about 0.1 mgof a presently disclosed compound, wherein cytokine levels and/oractivity (e.g., IL-2 levels and/or activity) are reduced by more thanabout 20% (e.g., as determined using a oxazolone-challenged atopicdermatitis mouse model).

According to one aspect, the present invention provides methods oftreating, ameliorating, controlling, or preventing inflammatory skinconditions such as atopic dermatitis comprising administering to asubject in need thereof a dosage form comprising at least about 0.1 mgof a presently disclosed compound, wherein cytokine levels and/oractivity (e.g., IL-6 levels and/or activity) are reduced by more thanabout 20% (e.g., as determined using an oxazolone-challenged atopicdermatitis mouse model).

According to one aspect, the present invention provides methods oftreating, ameliorating, controlling, or preventing inflammatory skinconditions such as atopic dermatitis comprising administering to asubject in need thereof a dosage form comprising at least about 0.1 mgof a presently disclosed compound, wherein cytokine levels and/oractivity (e.g., IL-8 levels and/or activity) are reduced by more thanabout 20% (e.g., as determined using an oxazolone-challenged atopicdermatitis mouse model).

According to one aspect, the present invention provides methods oftreating, ameliorating, controlling, or preventing inflammatory skinconditions such as atopic dermatitis comprising administering to asubject in need thereof a dosage form comprising at least about 0.1 mgof a presently disclosed compound, wherein cytokine levels and/oractivity (e.g., IL-12 levels and/or activity, IFN-γ levels and/oractivity, MCP-1 levels and/or activity or Gro-α levels and/or activity)are reduced by more than about 20% (e.g., as determined using anoxazolone-challenged atopic dermatitis mouse model).

Seborrhic Dermatitis

Seborrheic dermatitis, commonly called dandruff, is a disease thatcauses redness, itchiness, and flaking of the skin. It affects thescalp, face, trunk, and particularly the sebum-gland rich areas of theskin, usually causing the skin to look inflamed and scaly.

Seborrheic dermatitis most often occurs in adults from 30 to 60 years ofage and is more common in men than in women. Although the exact cause isnot known, those afflicted with seborrheic dermatitis often have anunfavorable epidermic response caused by infections. Seborrheicdermatitis has also been linked to neurologic disorders such asParkinson's disease and epilepsy. The treatment of seborrheic dermatitisdepends on its location on the body. Treatment also depends on theperson's age. Dandruff is often treated with a shampoo that containssalicylic acid, the prescription medicine selenium sulfide, zincpyrithione, ketoconazole or coal tar. Steroid lotions may be used inadolescents and adults. Exemplary cytokines associated with seborrhicdermatitis include, but are not limited to, TNFα, ILβ, IL-6, IL-8,MCP-1, and Groα.

Inflammatory Cytokines and Rosacea, Psoriasis, Atopic Dermatitis andSeborrhic Dermatitis

As described herein, the present invention provides methods of treatingameloriating, controlling, or preventing inflammatory skin conditions(e.g., rosacea, psoriasis, atopic dermatitis and seborrhic dermatitis).

In some embodiments, the present invention provides methods of treatingameloriating, controlling, or preventing inflammatory skin conditions(e.g., rosacea, psoriasis, atopic dermatitis and seborrhic dermatitis)by administering a presently disclosed compound, provided that at least0.1 mg of the compound is administered. In other embodiments, thepresent invention provides methods of treating ameloriating,controlling, or preventing inflammatory skin conditions (e.g., rosacea,psoriasis, atopic dermatitis and seborrhic dermatitis) by administeringa presently disclosed compound, provided that at least 2 mg of thecompound is administered.

According to one aspect, the present invention provides methods oftreating, ameliorating, controlling, or preventing inflammatory skinconditions (e.g., rosacea, psoriasis, atopic dermatitis and seborrhicdermatitis) comprising administering to a subject in need thereof adosage form comprising at least about 0.1 mg of a presently disclosedcompound, wherein inflammatory activity (e.g., MPO activity) is reducedby more than about 30% (e.g., as determined using an MPO activityassay).

According to one aspect, the present invention provides methods oftreating, ameliorating, controlling, or preventing inflammatory skinconditions (e.g., rosacea, psoriasis, atopic dermatitis and seborrhicdermatitis) comprising administering to a subject in need thereof adosage form comprising at least about 0.1 mg of a presently disclosedcompound, wherein inflammatory activity (e.g., MPO activity) is reducedby more than about 60% (e.g., as determined using an MPO activityassay).

According to one aspect, the present invention provides methods oftreating, ameliorating, controlling, or preventing inflammatory skinconditions (e.g., rosacea, psoriasis, atopic dermatitis and seborrhicdermatitis) comprising administering to a subject in need thereof adosage form comprising at least about 0.1 mg of a presently disclosedcompound, wherein inflammatory activity (e.g., erythema activity) isreduced by more than about 30% (e.g., as determined using an erythemaactivity assay).

According to one aspect, the present invention provides methods oftreating, ameliorating, controlling, or preventing inflammatory skinconditions (e.g., rosacea, psoriasis, atopic dermatitis and seborrhicdermatitis) comprising administering to a subject in need thereof adosage form comprising at least about 0.1 mg of a presently disclosedcompound, wherein inflammatory activity (e.g., edema activity) isreduced by more than about 30% (e.g., as determined using an edemaactivity assay).

In some embodiments, the present invention provides methods of treating,ameliorating, controlling, or preventing inflammatory skin conditions(e.g., rosacea, psoriasis, atopic dermatitis and seborrhic dermatitis)comprising administering to a subject in need thereof a dosage formcomprising at least about 0.1 mg of a presently disclosed compound,wherein cytokine levels and/or activity (e.g., TNF-α, levels and/oractivity) are reduced by more than about 20% (e.g., as determined usinga TPA-induced mouse ear inflammatory model).

In some embodiments, the present invention provides methods of treating,ameliorating, controlling, or preventing inflammatory skin conditions(e.g., rosacea, psoriasis, atopic dermatitis and seborrhic dermatitis)comprising administering to a subject in need thereof a dosage formcomprising at least about 0.1 mg of a presently disclosed compound,wherein cytokine levels and/or activity (e.g., IL-1β levels and/oractivity) are reduced by more than about 20% (e.g., as determined usinga TPA-induced mouse ear inflammatory model).

In some embodiments, the present invention provides methods of treating,ameliorating, controlling, or preventing inflammatory skin conditions(e.g., rosacea, psoriasis, atopic dermatitis and seborrhic dermatitis)comprising administering to a subject in need thereof a dosage formcomprising at least about 0.1 mg of a presently disclosed compound,wherein cytokine levels and/or activity (e.g., IL-8 levels and/oractivity) are reduced by more than about 20% (e.g., as determined usinga TPA-induced mouse ear inflammatory model).

In some embodiments, the present invention provides methods of treating,ameliorating, controlling, or preventing inflammatory skin conditions(e.g., rosacea, psoriasis, atopic dermatitis and seborrhic dermatitis)comprising administering to a subject in need thereof a dosage formcomprising at least about 0.1 mg of a presently disclosed compound,wherein cytokine levels and/or activity (e.g., IL-6 levels and/oractivity) are reduced by more than about 20% (e.g., as determined usinga TPA-induced mouse ear inflammatory model).

In some embodiments, the present invention provides methods of treating,ameliorating, controlling, or preventing inflammatory skin conditions(e.g., rosacea, psoriasis, atopic dermatitis and seborrhic dermatitis)comprising administering to a subject in need thereof a dosage formcomprising at least about 0.1 mg of a presently disclosed compound,wherein cytokine levels and/or activity (e.g., MCP-1 levels and/oractivity) are reduced by more than about 20% (e.g., as determined usinga TPA-induced mouse ear inflammatory model).

In some embodiments, the present invention provides methods of treating,ameliorating, controlling, or preventing inflammatory skin conditions(e.g., rosacea, psoriasis, atopic dermatitis and seborrhic dermatitis)comprising administering to a subject in need thereof a dosage formcomprising at least about 0.1 mg of a presently disclosed compound,wherein cytokine levels and/or activity (e.g., Groα levels and/oractivity) are reduced by more than about 20% (e.g., as determined usinga TPA-induced mouse ear inflammatory model).

In some embodiments, the present invention provides methods of treating,ameliorating, controlling, or preventing inflammatory skin conditions(e.g., rosacea, psoriasis, atopic dermatitis and seborrhic dermatitis)comprising administering to a subject in need thereof a dosage formcomprising at least about 0.1 mg of a presently disclosed compound,wherein cytokine levels and/or activity (e.g., TNF-α levels and/oractivity) are reduced by more than about 20% (e.g., as determined usingan LPS-TLR4-induced cytokine release inflammatory model in HMEC-1 cellline).

In some embodiments, the present invention provides methods of treating,ameliorating, controlling, or preventing inflammatory skin conditions(e.g., rosacea, psoriasis, atopic dermatitis and seborrhic dermatitis)comprising administering to a subject in need thereof a dosage formcomprising at least about 0.1 mg of a presently disclosed compound,wherein cytokine levels and/or activity (e.g., IL-1β levels and/oractivity) are reduced by more than about 20% (e.g., as determined usingan LPS-TLR4-induced cytokine release inflammatory model in HMEC-1 cellline).

In some embodiments, the present invention provides methods of treating,ameliorating, controlling, or preventing inflammatory skin conditions(e.g., rosacea, psoriasis, atopic dermatitis and seborrhic dermatitis)comprising administering to a subject in need thereof a dosage formcomprising at least about 0.1 mg of a presently disclosed compound,wherein cytokine levels and/or activity (e.g., IL-8/KC levels and/oractivity) are reduced by more than about 20% (e.g., as, determined usingan LPS-TLR4-induced cytokine release inflammatory model in HMEC-1 cellline).

In some embodiments, the present invention provides methods of treating,ameliorating, controlling, or preventing inflammatory skin conditions(e.g., rosacea, psoriasis, atopic dermatitis and seborrhic dermatitis)comprising administering to a subject in need thereof a dosage formcomprising at least about 0.1 mg of a presently disclosed compound,wherein cytokine levels and/or activity (e.g., IL-6 levels and/oractivity) are reduced by more than about 20% (e.g., as determined usingan LPS-TLR4-induced cytokine release inflammatory model in HMEC-1 cellline).

In some embodiments, the present invention provides methods of treating,ameliorating, controlling, or preventing inflammatory skin conditions(e.g., rosacea, psoriasis, atopic dermatitis and seborrhic dermatitis)comprising administering to a subject in need thereof a dosage formcomprising at least about 0.1 mg of a presently disclosed compound,wherein cytokine levels and/or activity (e.g., MCP-1 levels and/oractivity) are reduced by more than about 20% (e.g., as determined usingan LPS-TLR4-induced cytokine release inflammatory model in HMEC-1 cellline).

In some embodiments, the present invention provides methods of treating,ameliorating, controlling, or preventing inflammatory skin conditions(e.g., rosacea, psoriasis, atopic dermatitis and seborrhic dermatitis)comprising administering to a subject in need thereof a dosage formcomprising at least about 0.1 mg of a presently disclosed compound,wherein cytokine levels and/or activity (e.g., Gro-α levels and/oractivity) are reduced by more than about 20% (e.g., as determined usingan LPS-TLR4-induced cytokine release inflammatory model in HMEC-1 cellline).

In some embodiments, the present invention provides methods of treating,ameliorating, controlling, or preventing inflammatory skin conditions(e.g., rosacea, psoriasis, atopic dermatitis and seborrhic dermatitis)comprising administering to a subject in need thereof a dosage formcomprising at least about 0.1 mg of a presently disclosed compound,wherein cytokine levels and/or activity (e.g., TNF-α levels and/oractivity) are reduced by more than about 20% (e.g., as determined usingan ATPγS-purinergic receptor-induced cytokine release inflammatory modelin HMEC-1 cell line).

In some embodiments, the present invention provides methods of treating,ameliorating, controlling, or preventing inflammatory skin conditions(e.g., rosacea, psoriasis, atopic dermatitis and seborrhic dermatitis)comprising administering to a subject in need thereof a dosage formcomprising at least about 0.1 mg of a presently disclosed compound,wherein cytokine levels and/or activity (e.g., IL-1β levels and/oractivity) are reduced by more than about 20% (e.g., as determined usingan ATPγS-purinergic receptor-induced cytokine release inflammatory modelin HMEC-1 cell line).

In some embodiments, the present invention provides methods of treating,ameliorating, controlling, or preventing inflammatory skin conditions(e.g., rosacea, psoriasis, atopic dermatitis and seborrhic dermatitis)comprising administering to a subject in need thereof a dosage formcomprising at least about 0.1 mg of a presently disclosed compound,wherein cytokine levels and/or activity (e.g., IL-8/KC levels and/oractivity) are reduced by more than about 20% (e.g., as determined usingan ATPγS-purinergic receptor-induced cytokine release inflammatory modelin HMEC-1 cell line).

In some embodiments, the present invention provides methods of treating,ameliorating, controlling, or preventing inflammatory skin conditions(e.g., rosacea, psoriasis, atopic dermatitis and seborrhic dermatitis)comprising administering to a subject in need thereof a dosage formcomprising at least about 0.1 mg of a presently disclosed compound,wherein cytokine levels and/or activity (e.g., IL-6 levels and/oractivity) are reduced by more than about 20% (e.g., as determined usingan ATPγS-purinergic receptor-induced cytokine release inflammatory modelin HMEC-1 cell line).

In some embodiments, the present invention provides methods of treating,ameliorating, controlling, or preventing inflammatory skin conditions(e.g., rosacea, psoriasis, atopic dermatitis and seborrhic dermatitis)comprising administering to a subject in need thereof a dosage formcomprising at least about 0.1 mg of a presently disclosed compound,wherein cytokine levels and/or activity (e.g., MCP-1 levels and/oractivity) are reduced by more than about 20% (e.g., as determined usingan ATPγS-purinergic receptor-induced cytokine release inflammatory modelin HMEC-1 cell line).

In some embodiments, the present invention provides methods of treating,ameliorating, controlling, or preventing inflammatory skin conditions(e.g., rosacea, psoriasis, atopic dermatitis and seborrhic dermatitis)comprising administering to a subject in need thereof a dosage formcomprising at least about 0.1 mg of a presently disclosed compound,wherein cytokine levels and/or activity (e.g., Gro-α levels and/oractivity) are reduced by more than about 20% (e.g., as determined usingan ATPγS-purinergic receptor-induced cytokine release inflammatory modelin HMEC-1 cell line).

In some embodiments, the present invention provides methods of treating,ameliorating, controlling, or preventing inflammatory skin conditions(e.g., rosacea, psoriasis, atopic dermatitis and seborrhic dermatitis)comprising administering to a subject in need thereof a dosage formcomprising at least about 0.1 mg of a presently disclosed compound,wherein cytokine levels and/or activity (e.g., TNF-α levels and/oractivity) are reduced by more than about 20% (e.g., as determined usinga TPA-induced cytokine release inflammatory model in NHEK cell line).

In some embodiments, the present invention provides methods of treating,ameliorating, controlling, or preventing inflammatory skin conditions(e.g., rosacea, psoriasis, atopic dermatitis and seborrhic dermatitis)comprising administering to a subject in need thereof a dosage formcomprising at least about 0.1 mg of a presently disclosed compound,wherein cytokine levels and/or activity (e.g., IL-1β levels and/oractivity) are reduced by more than about 20% (e.g., as determined usinga TPA-induced cytokine release inflammatory model in NHEK cell line).

In some embodiments, the present invention provides methods of treating,ameliorating, controlling, or preventing inflammatory skin conditions(e.g., rosacea, psoriasis, atopic dermatitis and seborrhic dermatitis)comprising administering to a subject in need thereof a dosage formcomprising at least about 0.1 mg of a presently disclosed compound,wherein cytokine levels and/or activity (e.g., IL-8/KC levels and/oractivity) are reduced by more than about 20% (e.g., as determined usinga TPA-induced cytokine release inflammatory model in NHEK cell line).

In some embodiments, the present invention provides methods of treating,ameliorating, controlling, or preventing inflammatory skin conditions(e.g., rosacea, psoriasis, atopic dermatitis and seborrhic dermatitis)comprising administering to a subject in need thereof a dosage formcomprising at least about 0.1 mg of a presently disclosed compound,wherein cytokine levels and/or activity (e.g., IL-6 levels and/oractivity) are reduced by more than about 20% (e.g., as determined usinga TPA-induced cytokine release inflammatory model in NHEK cell line).

In some embodiments, the present invention provides methods of treating,ameliorating, controlling, or preventing inflammatory skin conditions(e.g., rosacea, psoriasis, atopic dermatitis and seborrhic dermatitis)comprising administering to a subject in need thereof a dosage formcomprising at least about 0.1 mg of a presently disclosed compound,wherein cytokine levels and/or activity (e.g., MCP-1 levels and/oractivity) are reduced by more than about 20% (e.g., as determined usinga TPA-induced cytokine release inflammatory model in NHEK cell line).

In some embodiments, the present invention provides methods of treating,ameliorating, controlling, or preventing inflammatory skin conditions(e.g., rosacea, psoriasis, atopic dermatitis and seborrhic dermatitis)comprising administering to a subject in need thereof a dosage formcomprising at least about 0.1 mg of a presently disclosed compound,wherein cytokine levels and/or activity (e.g., Gro-α levels and/oractivity) are reduced by more than about 20% (e.g., as determined usinga TPA-induced cytokine release inflammatory model in NHEK cell line).

In some embodiments, the present invention provides methods of treating,ameliorating, controlling, or preventing inflammatory skin conditions(e.g., rosacea, psoriasis, atopic dermatitis and seborrhic dermatitis)comprising administering to a subject in need thereof a dosage formcomprising at least about 0.1 mg of a presently disclosed compound,wherein cytokine levels and/or activity (e.g., TNF-α levels and/oractivity) are reduced by more than about 20% (e.g., as determined usinga TNFα-induced cytokine release inflammatory model in HUVEC cell line).

In some embodiments, the present invention provides methods of treating,ameliorating, controlling, or preventing inflammatory skin conditions(e.g., rosacea, psoriasis, atopic dermatitis and seborrhic dermatitis)comprising administering to a subject in need thereof a dosage formcomprising at least about 0.1 mg of a presently disclosed compound,wherein cytokine levels and/or activity (e.g., IL-1β levels and/oractivity) are reduced by more than about 20% (e.g., as determined usinga TNFα-induced cytokine release inflammatory model in HUVEC cell line).

In some embodiments, the present invention provides methods of treating,ameliorating, controlling, or preventing inflammatory skin conditions(e.g., rosacea, psoriasis, atopic dermatitis and seborrhic dermatitis)comprising administering to a subject in need thereof a dosage formcomprising at least about 0.1 mg of a presently disclosed compound,wherein cytokine levels and/or activity are reduced by more than about20%, such as IL-8/KC, determined using a TNFα-induced cytokine releaseinflammatory model in HUVEC cell line.

In some embodiments, the present invention provides methods of treating,ameliorating, controlling, or preventing inflammatory skin conditions(e.g., rosacea, psoriasis, atopic dermatitis and seborrhic dermatitis)comprising administering to a subject in need thereof a dosage formcomprising at least about 0.1 mg of a presently disclosed compound,wherein cytokine levels and/or activity (e.g., IL-6 levels and/oractivity) are reduced by more than about 20% (e.g., as determined usinga TNFα-induced cytokine release inflammatory model in HUVEC cell line).

In some embodiments, the present invention provides methods of treating,ameliorating, controlling, or preventing inflammatory skin conditions(e.g., rosacea, psoriasis, atopic dermatitis and seborrhic dermatitis)comprising administering to a subject in need thereof a dosage formcomprising at least about 0.1 mg of a presently disclosed compound,wherein cytokine levels and/or activity (e.g., MCP-1 levels and/oractivity) are reduced by more than about 20% (e.g., as determined usinga TNFα-induced cytokine release inflammatory model in HUVEC cell line).

In some embodiments, the present invention provides methods of treating,ameliorating, controlling, or preventing inflammatory skin conditions(e.g., rosacea, psoriasis, atopic dermatitis and seborrhic dermatitis)comprising administering to a subject in need thereof a dosage formcomprising at least about 0.1 mg of a presently disclosed compound,wherein cytokine levels and/or activity (e.g., Gro-α levels and/oractivity) are reduced by more than about 20% (e.g., as determined usinga TNFα-induced cytokine release inflammatory model in HUVEC cell line).

Sun Screen (Protection from UV Damage)

Oxidative stresses caused by environmental insults such as ultraviolet(“UV”) rays from the sun, cigarette smoke exposure, consumption of foodswith high saturated fat and environmental pollutants as well as thenatural process of aging, contributing to the generation of freeradicals and reactive oxygen species (“ROS”), stimulate inflammatoryresponses, especially in the skin (Pilla et al. Intl J. Cosm. Sci. 2005v27 p 17-34). High levels of ROS contribute to adverse effects on theskin including erythema, edema, photoaging and skin cancer (Trouba etal. Antioxid. Redox Signal 2002 v4 p 665-673). Neutrophil infiltrationduring inflammatory responses is associated with increased oxygenconsumption and generation of ROS. Extracellular inflammatory agonistssuch as fMLP bind to GPCRs such as formyl peptide receptors (“FPR”), totrigger the oxidative burst response (i.e., the rapid release of ROS).

In certain embodiments, the present invention provides methods oftreating, ameloriating, controlling, or preventing UV damage toespecially the skin of a subject, in need thereof, by administering apresently disclosed compound. In certain embodiments, at least 0.1 mg ofa presently disclosed compound is administered to treat, ameliorate,control, or prevent UV damage. In certain embodiments, the presentinvention provides methods of treating, ameloriating, controlling, orpreventing UV damage to especially the skin of a subject, in needthereof, by administering at least 2 mg of a presently disclosedcompound.

According to one embodiment, the present invention provides methods oftreating, ameliorating, controlling, or preventing UV damage toespecially the skin of a subject, in need thereof, comprisingadministering to a subject in need thereof a dosage form comprising atleast about 0.1 mg of a presently disclosed compound, having an activityin the inhibition of more than about 20% of superoxide formation.

(C) Anti-Bacterial

The presently disclosed compounds exhibit anti-bacterial activity andare useful in the inhibition of bacterial cell growth or bacterial celldeath or bacterial decolonization from surfaces. Thus, in certainembodiments, the presently disclosed compounds are useful in theinhibition of bacterial cell growth or bacterial cell death or bacterialdecolonization from surfaces, and/or in the treatment, prevention andmanagement of bacterial-associated conditions.

In some embodiments, the present invention provides, inter alia, methodsto treat, prevent or ameliorate the symptoms of epithelial-relateddiseases, disorders, or conditions, caused or aggravated by bacteria inanimals, particularly humans, in need of treatment thereof. In someembodiments, provided methods are useful for epithelial-relatedconditions (e.g. skin conditions, respiratory conditions, nasalconditions, ocular conditions, oral conditions, conditions of theexternal ear, vaginal conditions, genitourinary conditions, rectalconditions, bacterial-related conditions of similar tissues, etc.).

In some embodiments, exemplary skin conditions caused or aggravated bybacteria include, but are not limited to, impetigo; acne vulgaris;eczema; atopic dermatitis; infective dermatitis; psoriasis; rosacea;erythema; necrotizing cellulitis; cutaneous anthrax; cellulitis;erysipelas; ecthyma; cutaneous anthrax; necroticizing fasciitis;gangrene; septicaemia; pyoderma; endocarditis; toe web infections;sycosis barbae; furuncles and carbuncles; Staphylococcal scalded skinsyndrome; blistering distal dactylitis; acute paronychia; folliculitis;cutaneous diphtheria; erythrasma; and bacterial colonization of openwounds (e.g., cuts, lesions, scrapes, burns, lacerations, chronicwounds, infected animal bites, ulcerations, etc.).

In some embodiments, exemplary respiratory conditions caused oraggravated by bacteria include, but are not limited to, pneumonia;hypersensitivity pneumonitis; upper and lower respiratory tractinfections (e.g., secondary bacterial infections in chronic bronchitis,asthma, etc.); chronic obstructive pulmonary disease; diphtheria;bronchopulmonary dysplasia; pertussis; legionellosis (e.g.,Legionnaires' disease, Pontiac fever; pharyngitis, etc.).

In some embodiments, exemplary nasal conditions caused or aggravated bybacteria include bacterial rhinitis; paranasal sinusitis, etc.

In some embodiments, exemplary ocular conditions caused or aggravated bybacteria include chronic blepharitis; endophthalmitis, etc.

In some embodiments, exemplary oral conditions caused or aggravated bybacteria include gingivitis; dental caries; early childhood caries, etc.

In some embodiments, exemplary conditions of the external ear caused oraggravated by bacteria include otitis media, etc.

In some embodiments, exemplary vaginal conditions caused or aggravatedby bacteria include bacterial vaginosis; chanchroid; syphilis;donovanosis; gonorrhea; lymphogranuloma venereum; non-gonococcalurethritis; staphylococcal infection, vulvovaginitis; etc.

In some embodiments, exemplary genitourinary conditions caused oraggravated by bacteria include for example, Granuloma inquinale,perianal infections, etc.

In some embodiments, bacteria inhibited by the presently disclosedcompounds include Gram positive bacteria. In some embodiments, bacteriainhibited by the presently disclosed compounds include Gram negativebacteria. In some embodiments, bacteria inhibited by the presentlydisclosed compounds include Gram variable bacteria. Particularlyrelevant Gram positive bacteria include, for example, Actinomyces sp.(e.g., Actinomyces israelli, etc.); Bacillus sp. (e.g., Bacillusanthracis, etc.); Corynebacterium sp. (e.g., Corynebacteriumdiphtheriae, etc.); Enterococcus sp (e.g., Enterococcus faecalis, etc.);Gardnerella sp. (e.g., Gardnerella vaginalis, etc.); Mobiluncus sp.(e.g., Mobiluncus curtisii, Mobiluncus mulieris, etc.); Mycobacteriumsp. (e.g., Mycobacterium immunogenum, Mycobacterium tuberculosis, etc.);Mycoplasma sp. (e.g., Mycoplasma pneumonia, Mycoplasma hyopneumoniae,Mycoplasma gallisepticum, Mycoplasma synoviae, Mycoplasma meleagridis,Mycoplasma gallinarum, Mycoplasma anatis, Mycoplasma hominis, etc.);Nocardia sp. (e.g., Nocardia asteroides, Nocardia brasiliensis, Nocardiacaviae, etc.); Propionibacterium sp. (e.g., Propionibacterium acnes,Propionibacterium propionicus, Propionibacterium freudenreichii, etc.);Staphylococcus sp. (e.g., Staphylococcus aureus, Staphylococcuspseudintermedius, Staphylococcus epidermidis, Staphylococcussaprophyticus, Staphylococcus pyogenes, etc.); Streptococcus sp. (e.g.,Streptococcus pneumoniae, Streptococcus mutans, Streptococcus mitis,Streptococcus salivarius, Streptococcus pyogenes, etc.).

Particularly relevant Gram negative bacteria include, for example,Actinobacillus sp. (e.g., Actinobacillus pleuropneumoniae, etc.);Bordatella sp. (e.g., Bordatella pertussis, etc.); Branhamella(Moraxella) sp. (e.g., Branhamella catarrhalis, etc.);Calymmatobacterium sp. (e.g., Calymmatobacterium granulomatis, etc.);Chlamydia sp. (e.g., Chlamydia trachomatis, etc.); Chlamydophila sp.(e.g., Chlamydophila pneumoniae, etc.); Eikenella sp. (e.g., Eikenellacorrodens, etc.); Enterobacter sp. (e.g., Enterobacter aerogenes,Enterobacter cloacae, etc.); Escherichia sp. (e.g., Escherichia coli,etc.); Fusobacterium sp. (e.g., Fusobacterium nucleatum, etc.);Gardnerella sp. (e.g., Gardnerella vaginalis, etc.); Haemophilus sp.(e.g., Haemophilus influenza, Haemophilus ducreyi, etc.); Histophilussp. (e.g., Histophilus somnus, etc.); Klebsiella sp. (e.g., Klebsiellapneumoniae, etc.); Legionella sp. (e.g., Legionella pneumophila, etc.);Mannheimia sp. (e.g., Mannheimia haemolytica, etc.); Neisseria sp.(e.g., Neisseria gonorrhoeae, etc.); Ornithobacterium sp. (e.g.,Ornithobacterium rhinotracheale, etc.); Pasteurella sp. (e.g.,Pasteurella multocida, etc.); Pneumocystis sp. (e.g., Pneumocystiscarinii, etc.); Prevotella sp. (e.g., Prevotella melaninogenica,Prevotella intermedia, etc.); Proteus sp. (e.g., Proteus vulgaris,Proteus mirabilis, Proteus penneri, etc.); Psuedomonas sp. (e.g.,Psuedomonas aeruginosa, etc.); Treponema sp. (e.g., Treponema pallidum,etc.); Ureaplasma sp. (e.g., Ureaplasma urealyticum, etc.); Vibrio sp.(e.g., Vibrio vulnificus, etc.); Yersinia sp. (e.g., Yersinia pestis,etc.), etc. Particularly relevant Gram variable bacteria include, forexample, Gardnerella sp. (e.g., Gardnerella vaginalis, etc.).

In some embodiments, the present invention provides, inter alia, methodsto treat, prevent or ameliorate the symptoms of acne. Propionibacteriumacnes (P. acnes) is a major contributing factor to acne vulgaris, acommon disorder among postpubescent teens that is estimated to affect9.4% of the global population.

Comedones, the primary acne lesions, are the result of abnormalfollicular keratinization related to excessive sebum secretion. P. acnescolonize and proliferate within the pilosebaceous follicles causing theinduction of a local inflammatory response. This is mediated through theinteraction of P. acnes with epidermal keratinocytes leading toactivation of toll-like receptor (TLR2) and later resulting in theproduction and secretion of pro-inflammatory mediators. Moreparticularly, the interaction of bacterial cell-wall componentsincluding peptidoglycan (PGN) and lipopolysaccharides (LPS) withkeratinocytes (NHEK) leads to an innate immune response via activationof toll-like receptors (TLR2, TLR4) resulting in the production andsecretion of pro-inflammatory mediators.

In certain embodiments of the present invention, presently disclosedcompounds down regulate these inflammatory signaling pathways anddirectly decrease P. acnes viability. As detailed in greater detail inthe Examples, cultured human keratinocytes were exposed to P. acnes andpeptidoglycan (PGN) to induce pro-inflammatory cytokine production. Inthese cell-based models, compounds of the present invention (e.g.,compounds E and G) inhibit IL-8 production versus both TLR2 inducers. Inan in vitro growth inhibition assay of cultured P. acnes, presentlydisclosed compounds outperform commonly applied anti-acne agents,benzoyl peroxide and salicylic acid, exhibiting a minimal inhibitoryconcentration (MIC) of 3-4 μg/mL. These data demonstrate that presentlydisclosed compounds represent a novel chemical-class that provides adual modulating anti-acne benefit by (a) limiting P. acnes bacterialproliferation and (b) inhibiting inflammation by down regulatinginflammatory signaling pathways (e.g., activation of toll-like receptors(TLR2, TLR4) resulting in the production and secretion ofpro-inflammatory mediators).

7. Combination Therapy

It is contemplated that a presently disclosed compound can be used incombination with other drugs or therapeutic agents.

In some embodiments, a presently disclosed compound as described hereinare administered in combination with one or more other agents intendedto treat the same condition, or disease. As used herein, additionaltherapeutic agents that are normally administered to treat a particulardisease, or condition, are known as “appropriate for the disease, orcondition, being treated.”

For example, in some embodiments, compounds of the present invention, ora pharmaceutically acceptable composition thereof, are administered incombination with other anti-inflammatory agents to treat inflammatorydiseases and/or disorders. Examples of known anti-inflammatory agentsinclude, but are not limited to, dexamethasone, indomethacin andclobetasol.

In some embodiments, a presently disclosed compound is administered incombination with one or more other pharmaceutically active agentsintended to treat a different disease, disorder, or condition. Forexample, in some embodiments, it may be desirable to administer apresently disclosed compound in order to reduce inflammation whileconcurrently administering a different pharmaceutically active agent inorder to achieve a different biological result.

To give but one example, it is not uncommon that a skin irritating agent(e.g., sodium dodecyl sulfate) be administered prior to or concurrentwith application of a transdermal device such as, for example, atransdermal patch, in order to facilitate the delivery. Alternatively,addition or co-administration of a presently disclosed compound incombination with transdermal administration of another pharmaceuticallyactive agent can reduce inflammation and/or irritation associated withthe transdermal administration of the other pharmaceutically activeagent.

It is also known that single or chronic injections of a pharmaceuticallyactive agent may sometimes result in inflammation, whether due to theidentity of the pharmaceutically active agent (i.e., as an irritant) orto the mode of delivery. The present invention contemplatesco-administration of one or more compounds of the present invention, inorder to reduce inflammation associated with single or chronic injectionof a pharmaceutically active agent.

Exemplary pharmaceutically active agents whose delivery, whethertransdermally or by injection, may cause skin irritation includelevadopa, pro-drug forms of levadopa, insulin, estradiol, estrogen,progesterone, progestins, progestogen, testosterone, nicotine,nitroglycerin, cholinesterase inhibitors, stimulants, antidepressants,and analgesics.

To give another example, application of certain agents such as, forexample, hair relaxants, which commonly are or contain basic agents(e.g., NaOH), can cause skin irritation (e.g., irritation and/orinflammation of the scalp). According to the present invention, one ormore presently disclosed compound can be administered together with sucha hair relaxant (or other agent) to reduce skin irritation and/orinflammation.

Although the invention has been described in detail with particularreference to these preferred embodiments, other embodiments can achievethe same results. Variations and modifications of the present inventionwill be obvious to those skilled in the art and it is intended to coverall such modifications and equivalents. The entire disclosures of allreferences, applications, patents, and publications cited above and/orin the attachments, and of the corresponding application(s), are herebyincorporated by reference.

EXAMPLES

As depicted in the Examples below, in certain exemplary embodiments,compounds are prepared according to the following general procedures. Itwill be appreciated that, although the general methods depict thesynthesis of certain compounds of the present invention, the followinggeneral methods, and other methods known to one of ordinary skill in theart, can be applied to all classes, subclasses and species of each ofthese compounds, disclosed herein.

Example 1 Synthesis ofdisodium(2R)-2-{[(carboxylatomethyl)(methyl)carbamoyl]amino}-3-{[(2E)-3,7,11,15-tetramethylhexadec-2-en-1-yl]sulfanyl}propanoate

A solution of toluene (99.5+%, CAS [108-88-3], Aldrich) and phosphoroustribromide (99+%, CAS [7789-60-8], Aldrich) is added to a mixture of acommercially phytol (97%, CAS [7541-49-3], toluene, and triethylamine(99.5+%, CAS [121-44-8], Aldrich) at a controlled rate keeping thetemperature in the pot below 10° C. The mixture is warmed to 20-25° C.and sampled for reaction completion. The reaction is quenched withagitation by the addition of water, keeping the temperature below 25° C.The mixture is stirred to dissolve all phosphorous acid amine salts andthen allowed to settle. The lower aqueous layer is split off and theorganic layer washed with 15% brine, settled, and split. The organiclayer is recovered and then vacuum stripped to remove the toluene fromthe desired phytyl bromide. Commercial L-cysteine methyl ester (98%,[18598-63-5], Aldrich) and isopropanol (99.5%, [67-63-0], Aldrich) arecharged to a kettle at 24° C. Sodium carbonate (99.5%, powder,[497-19-8], Aldrich) is added through a star valve to form the sodiumsalt of L-cysteine plus carbon dioxide. The mixture is then vigorouslystirred and phytyl bromide is added slowly. The mixture is sampled forreaction completion and then isopropanol is removed under reducedpressure. Water is added to quench the reaction and dissolve the solidsand then pH is adjusted to 7 with 2N HCl. The mixture is stirred for 30min to ensure complete hydrolysis of any traces of phytyl bromide(monitored by HPLC), settled, and the amorphous solid is separated byfiltration. The solid is dissolved in the THF (>99.9%, [109-99-9]Aldrich) and CDI (>97%, [530-62-1], Aldrich) are added, followed byaddition of triethylamine (99.5+%, CAS [121-44-8], Aldrich). Finally,sarcosine methyl ester hydrochloride (98%, [13515-93-0], Aldrich) wasadded and the reaction mixture was heated to 50° C. Upon coolingreaction is quenched with water and pH is adjusted to 3 with 2N HClfollowed by splitting off the bottom layer and the additional wash withbrine. Then the organic layer was treated with LiOH (aqueous; 1N),followed by adjusting pH to 3 with 2N HCl. The organic layer wasseparated, dried over magnesium sulfate, filtered and concentrated toyield a glassy solid, which is re-dissolved in ethanol followed byformation of its disodium salt with the appropriate sodium hydroxide.The final productdisodium(2R)2{[(carboxylatomethyl)-(methyl)carbamoyl]amino}-3-{[(2E)-3,7,11,15-tetramethylhexadec-2-en-1-yl]sulfanyl}propanoateis separated by filtration, dried in the vacuum oven at 25° C. andpackaged under nitrogen in glass jars in a 61% yield.

This synthesis scheme is summarized below:

Example 2 Synthesis of Disodium(2R)-2-{[(carboxylatomethyl)(ethyl)carbamoyl]amino}-3-{[(2E)-3,7,11,15-tetramethylhexadec-2-en-1-yl]sulfanyl}propanoate

A solution of toluene (99.5+%, CAS [108-88-3], Aldrich) and phosphoroustribromide (99+%, CAS [7789-60-8], Aldrich) is added to a mixture of acommercially phytol (97%, CAS [7541-49-3], toluene, and triethylamine(99.5+%, CAS [121-44-8], Aldrich) at a controlled rate keeping thetemperature in the pot below 10° C. The mixture is warmed to 20-25° C.and sampled for reaction completion. The reaction is quenched withagitation by the addition of water, keeping the temperature below 25° C.The mixture is stirred to dissolve all phosphorous acid amine salts andthen allowed to settle. The lower aqueous layer is split off and theorganic layer washed with 15% brine, settled, and split. The organiclayer is recovered and then vacuum stripped to remove the toluene fromthe desired phytyl bromide. Commercial L-cysteine methyl ester (98%,[18598-63-5], Aldrich) and isopropanol (99.5%, [67-63-0], Aldrich) arecharged to a kettle at 24° C. Sodium carbonate (99.5%, powder,[497-19-8], Aldrich) is added through a star valve to form the sodiumsalt of L-cysteine plus carbon dioxide. The mixture is then vigorouslystirred and phytyl bromide is added slowly. The mixture is sampled forreaction completion and then isopropanol is removed under reducedpressure. Water is added to quench the reaction and dissolve the solidsand then pH is adjusted to 7 with 2N HCl. The mixture is stirred for 30min to ensure complete hydrolysis of any traces of phytyl bromide(monitored by HPLC), settled, and the amorphous solid is separated byfiltration. The solid is dissolved in the THF (>99.9%, [109-99-9]Aldrich) and CDI (>97%, [530-62-1], Aldrich) are added, followed byaddition of triethylamine (99.5+%, CAS [121-44-8], Aldrich). Finally,N-Ethyl Glycine methyl ester hydrochloride (97%, [1121527-61-4],Enamine) was added and the reaction mixture was heated to 50° C. Uponcooling reaction is quenched with water and pH is adjusted to 3 with 2NHCl followed by splitting off the bottom layer and the additional washwith brine. Than the organic layer was treated with LiOH (aqueous; 1N),followed by adjusting pH to 3 with 2N HCl. The organic layer wasseparated, dried over magnesium sulfate, filtered and concentrated toyield a glassy solid, which is re-dissolved in ethanol followed byformation of its disodium salt with the appropriate sodium hydroxide.The final product disodium(2R)-2-{[(carboxylatomethyl)(ethyl)carbamoyl]amino}-3-{[(2E)-3,7,11,15-tetramethylhexadec-2-en-1yl]sulfanyl}-propanoate is separated by filtration, dried in the vacuumoven at 25° C. and packaged under nitrogen in glass jars in 48% yield.

This synthesis scheme is summarized below:

Example 3 Synthesis of (disodium(2S)-1-{[(1R)-1-carboxylato-2-{[(2E)-3,7,11,15-tetramethylhexadec-2-en-1-yl]sulfanyl}ethyl]carbamoyl}pyrrolidine-2-carboxylate)

A solution of toluene (99.5+%, CAS [108-88-3], Aldrich) and phosphoroustribromide (99+%, CAS [7789-60-8], Aldrich) is added to a mixture of acommercially phytol (97%, CAS [7541-49-3], toluene, and triethylamine(99.5+%, CAS [121-44-8], Aldrich) at a controlled rate keeping thetemperature in the pot below 10° C. The mixture is warmed to 20-25° C.and sampled for reaction completion. The reaction is quenched withagitation by the addition of water, keeping the temperature <25° C. Themixture is stirred to dissolve all phosphorous acid amine salts and thenallowed to settle. The lower aqueous layer is split off and the organiclayer washed with 15% brine, settled, and split. The organic layer isrecovered and then vacuum stripped to remove the toluene from thedesired phytyl bromide. Commercial L-cysteine methyl ester (98%,[18598-63-5], Aldrich) and isopropanol (99.5%, [67-63-0], Aldrich) arecharged to a kettle at 24° C. Sodium carbonate (99.5%, powder,[497-19-8], Aldrich) is added through a star valve to form the sodiumsalt of L-cysteine plus carbon dioxide. The mixture is then vigorouslystirred and phytyl bromide is added slowly. The mixture is sampled forreaction completion and then isopropanol is removed under reducedpressure. Water is added to quench the reaction and dissolve the solidsand then pH is adjusted to 7 with 2N HCl. The mixture is stirred for 30min to ensure complete hydrolysis of any traces of phytyl bromide(monitored by HPLC), settled, and the amorphous solid is separated byfiltration. The solid is dissolved in the THF (>99.9%, [109-99-9]Aldrich) and CDI (>97%, [530-62-1], Aldrich) are added, followed byaddition of trimethylamine (99.5+%, CAS [121-44-8], Aldrich). Finally,proline methyl ester hydrochloride (98%, [2133-40-6], Aldrich) was addedand the reaction mixture was heated to 50° C. Upon cooling reaction isquenched with water and pH is adjusted to 3 with 2N HCl followed bysplitting off the bottom layer and the additional wash with brine. Thanthe organic layer was treated with LiOH (aqueous; 1N), followed byadjusting pH to 3 with 2N HCl. The organic layer was separated, driedover magnesium sulfate, filtered and concentrated to yield a glassysolid which is re-dissolved in ethanol followed by formation of itsdisodium salt with the appropriate sodium hydroxide. The final product(disodium(2S)-1-{[(1R)-1-carboxylato-2-{[(2E)-3,7,11,15-tetramethylhexadec-2-en-1-yl]sulfanyl}ethyl]carbamoyl}pyrrolidine-2-carboxylate)is separated by filtration, dried in the vacuum oven at 25° C. andpackaged under nitrogen in glass jars in 67% yield.

This reaction scheme is summarized below:

Example 4 Synthesis of (trisodium(2R)-2-{[bis(carboxylatomethyl)carbamoyl]amino}-3-{[(2E)-3,7,11,15-tetramethylhexadec-2-en-1-yl]sulfanyl}propanoate

A solution of toluene (99.5+%, CAS [108-88-3], Aldrich) and phosphoroustribromide (99+%, CAS [7789-60-8], Aldrich) is added to a mixture of acommercially phytol (97%, CAS [7541-49-3], toluene, and triethylamine(99.5+%, CAS [121-44-8], Aldrich) at a controlled rate keeping thetemperature in the pot below 10° C. The mixture is warmed to 20-25° C.and sampled for reaction completion. The reaction is quenched withagitation by the addition of water, keeping the temperature below 25° C.The mixture is stirred to dissolve all phosphorous acid amine salts andthen allowed to settle. The lower aqueous layer is split off and theorganic layer washed with 15% brine, settled, and split. The organiclayer is recovered and then vacuum stripped to remove the toluene fromthe desired phytyl bromide. Commercial L-cysteine methyl ester (98%,[18598-63-5], Aldrich) and isopropanol (99.5%, [67-63-0], Aldrich) arecharged to a kettle at 24° C. Sodium carbonate (99.5%, powder,[497-19-8], Aldrich) is added through a star valve to form the sodiumsalt of L-cysteine plus carbon dioxide. The mixture is then vigorouslystirred and phytyl bromide is added slowly. The mixture is sampled forreaction completion and then isopropanol is removed under reducedpressure. Water is added to quench the reaction and dissolve the solidsand then pH is adjusted to 7 with 2N HCl. The mixture is stirred for 30min to ensure complete hydrolysis of any traces of phytyl bromide(monitored by HPLC), settled, and the amorphous solid is separated byfiltration. The solid is dissolved in the THF (>99.9%, [109-99-9]Aldrich) and CDI (>97%, [530-62-1], Aldrich) are added, followed byaddition of triethylamine (99.5+%, CAS [121-44-8], Aldrich). Finally,dimethyl 2,2′-iminodiacetate (98%, [6096-81-7], MolBase) was added andthe reaction mixture was heated to 50° C. Upon cooling reaction isquenched with water and pH is adjusted to 3 with 2N HCl followed bysplitting off the bottom layer and the additional wash with brine. Thanthe organic layer was treated with LiOH (aqueous; 1N), followed byadjusting pH to 3 with 2N HCl. The organic layer was separated, driedover magnesium sulfate, filtered and concentrated to yield a glassysolid which is re-dissolved in ethanol followed by formation of itsdisodium salt with the appropriate sodium hydroxide. The final product(trisodium(2R)-2-{[bis(carboxylatomethyl)carbamoyl]amino}-3-{[(2E)-3,7,11,15-tetramethylhexadec-2-en-1-yl]sulfanyl}propanoateis separated by filtration, dried in the vacuum oven at 25° C. andpackaged under nitrogen in glass jars in 70% yield.

This synthesis scheme is summarized below:

Example 5 Synthesis of DisodiumN-(2-(carboxylatomethoxy)acetyl)-S-((E)-3,7,11,15-tetramethylhexadec-2-en-1-yl)-L-cysteinate

The titled compound was prepared by the synthesis scheme set forthbelow:

Example 6 Synthesis of(2S)-1-{[(1R)-1-carboxy-2-{[(2E)-3,7,11,15-tetramethylhexadec-2-en-1-yl]sulfanyl}ethyl]carbamoyl}piperidine-2-carboxylicacid

The following general experimental procedures were used for Examples6-35 as described below. Proton Nuclear Magnetic Resonance (¹HNMR)spectroscopy was recorded on a Bruker 500 MHz spectrometer, dimethylsulfoxide (DMSO-d6), methanol (CD₃OD) or chloroform (CDCl₃) was used asthe ¹H-NMR solvent. The residual proton absorption of the deuteratedsolvent was used as the internal standard. All ¹H-NMR chemical shift arereported as δ values in the parts per million (ppm). The splittingpattern abbreviations are as follows: s, singlet; d, doublet; t,triplet; q, quartet; br, broad; m, multiplet; dd, doublet of doublet;dt, doublet of triplets. The HPLC analysis was done using a phenomenexluna C₁₈(2)50×4.6 mm column. The mobile phase is 60% water, 40%acetonitrile containing 0.05% trifluoroacetic acid at 2 ml per minuteflow rate for the first 2.5 minutes, followed by a gradient to 100%acetonitrile containing 0.05% TFA over 10 minutes. The eluent wasobserved at 214 nm.

The titled compound, shown above, was prepared according to the generalprocedure described in Examples 1-5. The prepared compound wascharacterized as follows: 1H-NMR (500 MHz, CDCl3) δ 0.78 (m, 12H),1.21-1.64 (m, 26H), 1.72 (s, 3H), 1.76 (m, 1H), 2.02 (br s, 3H), 2.48(br s, 1H), 2.27 (t, 1H), 3.42 (m, 4H), 3.81 (dd, 1H), 4.27 (dd, 1H),4.82 (t, 1H), 5.20 (t, 1H); 13C-NMR (125 MHz, CDCl3) δ 16.1, 19.1, 21.9,23.7, 25.4, 25.6, 25.7, 26.2, 26.7, 34.4, 37.8, 38.0, 38.2, 38.9, 39.3,40.2, 40.6, 47.7, 53.0, 116.3, 137.4, 140.3, 150.2, 167.2, 168.7.

Example 7 Synthesis of trisodium(2R)-2-{[bis(carboxylatomethyl)carbamoyl]amino}-3-(methylsulfanyl)propanoate

S-Methyl cysteine methyl ester (500 mg, 2.69 mmol) was suspended in THF(10 mL) followed by addition of Hunigs base (470 uL, 2.69 mmol),followed by CDI (611 mg, 3.23 mmol). The reaction was stirred for 2 hrsat room temperature and was monitored by TLC. Once the starting materialwas consumed, diethyliminoacetate (414 uL, 2.69 mmol) was added andreaction was further stirred overnight. The reaction mixture wasconcentrated partitioned between EtOAc (20 mL) and water (20 mL). Theorganic layer was dried over sodium sulfate, passed through a silica gelplug and concentrated. The resulting trimester derivative was dissolvedin THF (10 mL) and 1N NaOH (3 mL) was added. The reaction mixture wasstirred at room temperature for 6 hrs, then acidified with 1N HCl (4 mL)and extracted with EtOAc (3×10 mL). The organic layer was dried overmagnesium sulfate and concentrated to yield the titled compound (235 mg,29%).

This compound was characterized as follows. (535 mg, 82% yield): ¹H-NMR(500 MHz, D₂O) δ 2.11 (s, 3H), 2.72 (dd, 1H), 2.81 (dd, 1H), 3.70 (m,2H), 3.82 (d, 2H), 4.26 (dd, 1H); ¹³C-NMR (125 MHz, D₂O) δ 25.7, 36.6,52.2, 55.1, 158.3, 178.2, 182.5.

Example 8 Synthesis of2-{[(adamantan-1-yl)carbamoyl](carboxymethyl)amino}acetic acid

To a solution of adamantylisocyanate (500 mg, 2.82 mmol) in DCMdiethyliminoacetate (433 uL, 2.82 mmol) was added and the reactionmixture was stirred for 2 hrs at room temperature. The reaction wasmonitored by TLC. The reaction mixture was concentrated and re-dissolvedin THD (10 mL). 1N NaOH (6 mL) was added and the mixture was stirred for4 hrs at room temperature. The hydrolysis was monitored by HPLC. Theproduct was isolated by adding 1N HCl (8 mL) followed by extraction withEtOAc. The organic layer was dried over sodium sulfate and concentratedto yield the titled compound (743 mg, 85%) as a white solid.

This compound was characterized as follows. ¹H-NMR (500 MHz, CDCl₃) δ1.62 (m, 6H), 2.03 (m, 9H), 4.02 (s, 4H), 4.98 (s, 1H); ¹³C-NMR (125MHz, CDCl₃) δ 29.2, 38.7, 41.9, 51.6, 158.1, 171.2;

Example 9 Synthesis of1-{[(1R)-1-carboxy-2-{[(2E)-3,7,11,15-tetramethylhexadec-2-en-1-yl]sulfanyl}ethyl]carbamoyl}azetidine-2-carboxylic

The titled compound, shown above, was prepared according to the generalprocedure described in Examples 1-5. The prepared compound wascharacterized as follows: ¹H-NMR (500 MHz, CDCl₃) δ 0.79 (m, 12H),1.19-1.61 (m, 24H), 1.66 (m, 1H), 1.71 (s, 3H), 1.98 (br s, 3H), 2.84(m, 2H), 3.27 (m, 2H), 3.47 (m, 1H), 4.24 (m, 2H), 4.59 (m, 1H), 5.22(m, 1H); ¹³C-NMR (125 MHz, CDCl₃) δ 17.3, 20.1, 20.8, 23.7, 26.1, 26.3,26.6, 29.8, 34.2, 38.7, 39.1, 39.4, 39.9, 53.2, 54.4 117.5, 142.2,158.8, 167.1, 168.7.

Example 10 Synthesis of6-{[(2E)-3,7,11,15-tetramethylhexadec-2-en-1-yl]sulfanyl}pyridine-3-carboxylicacid

To a solution of phytyl cysteine methyl ester (464 mg; 1.03 mmol) and2-chloro-5-methylcarboxylate-pyridine (181 mg; 1.03 mmol) in isopropanol(5 mL) Cs₂CO₃ (738 mg; 2.27 mmol) was added. The reaction mixture washeated for 4 hrs to a gentle reflux and monitored by HPLC. Once thestarting material was fully consumed, the reaction mixture wasconcentrated and THF (2 mL) was added followed by 1N NaOH (2 mL). Theresulting mixture was stirred overnight at room temperature. After 16hrs HPLC indicated that diester intermediate was fully hydrolized andreaction mixture was acidified with 1N HCl to pH 3 and extracted withEtOAc (2×10 mL). The organic layer was concentrated and the product (28mg; 7% yield) was isolated by column chromatography.

The titled compound was characterized as follows: ¹H-NMR (500 MHz,CDCl₃) δ 0.88 (m, 12H), 1.21-1.65 (m, 18H), 1.66 (m, 1H), 1.71 (s, 3H),1.98 (br s, 3H), 2.21 (m, 2H), 3.77 (m, 1H), 5.27 (m, 1H); ¹³C-NMR (125MHz, CDCl₃) δ 17.9, 18.6, 20.3, 20.4, 20.6, 20.8, 29.0, 30.5, 39.4,109.2, 114.1, 124.7, 137.9, 139.2, 150.1, 162.2, 172.0.

Example 11 Synthesis of2-{[(1R)-1-carboxy-2-{[(2E)-3,7,11,15-tetramethylhexadec-2-en-1-yl]sulfanyl}ethyl]amino}-4-(trifluoromethyl)pyrimidine-5-carboxylicacid disodium

To a solution of phytyl cysteine methyl ester (464 mg; 1.03 mmol) and2-chloro-4-trifluoromethyl-5-methylcarboxylate-pyrimidine (262 mg; 1.03mmol) in isopropanol (5 mL) Cs2CO3 (738 mg; 2.27 mmol) was added. Thereaction mixture was heated for 4 hrs to a gentle reflux and monitoredby HPLC. Once the starting material was fully consumed, the reactionmixture was concentrated and THF (2 mL) was added followed by 1N NaOH (2mL). The resulting mixture was stirred overnight at room temperature.After 16 hrs HPLC indicated that diester intermediate was fullyhydrolized and reaction mixture was acidified with 1N HCl to pH 3 andextracted with EtOAc (2×10 mL). The organic layer was concentrated andthe product (211 mg; 34% yield) was isolated by column chromatography.The titled compound was characterized as follows: ¹H-NMR (500 MHz,CDCl₃) δ 0.87 (m, 12H), 1.21-1.63 (m, 22H), 1.68 (m, 1H), 1.77 (s, 3H),2.03 (br s, 2H), 3.07-3.22 (m, 3H), 4.58 (m, 1H), 5.29 (m, 1H); ¹³C-NMR(125 MHz, CDCl₃) δ 14.9, 18.8, 20.2, 20.5, 20.6, 20.7, 28.8, 30.7, 39.2,39.5, 52.1, 110.5, 119.9, 126.6, 126.9, 129.6, 131.6, 139.1, 139.6,161.9, 172.1.

Example 12 Synthesis of disodium(2R)-2-[2-(carboxylatomethoxy)acetamido]-3-{[(2E)-3,7,11,15-tetramethylhexadec-2-en-1-yl]sulfanyl}propanoate

Diglycolic anhydride (154 mg, 1.33 mmol) was added to a stirringsolution of phytyl cysteine methyl ester (500 mg, 1.21 mmol) in THF (10mL) at room temperature. The reaction mixture was heated at 50° C. for30 minutes, at which time the reaction was complete by HPLC. The crudereaction mixture was then cooled to room temperature, and a 1M solutionof lithium hydroxide (5 mL) was added at room temperature. Enoughmethanol was added to the bi-phasic mixture so that it became ahomogenous solution and was stirred at 50° C. for 1 hour. The reactionwas monitored by HPLC for completion. Upon completion, the reaction wascooled to room temperature, diluted in ethyl acetate, washed once with a1N HCl solution, once with brine and dried over magnesium sulfate. Theethyl acetate was filtered, and concentrated to dryness on a rotaryevaporator to give 354 mg of the product as a brown oil in 56% yield.The titled compound was characterized as follows: ¹H NMR (500 MHz,Chloroform-d) δ 8.39 (s, 2H), 7.89 (d, J=8.4 Hz, 1H), 5.35-5.16 (m, 1H),4.89 (ddd, J=8.5, 6.7, 4.9 Hz, 1H), 4.43-4.26 (m, 2H), 4.22-4.09 (m,2H), 3.48-3.15 (m, 2H), 3.07-2.86 (m, 2H), 2.05-1.94 (m, 2H), 1.69 (s,3H), 1.54 (dp, J=13.2, 6.6 Hz, 1H), 1.44-1.02 (m, 19H), 0.92-0.83 (m,12H).

Example 13 Synthesis of(2R)-2-{[(carboxymethyl)(methyl)carbamoyl]amino}-3-{[(2E)-3,7,11,15-tetramethylhexadec-2-en-1-yl]sulfanyl}propanoicacid

Carbonyl diimidazole (107 mg, 1.2 mmol) was added to a solution ofphytyl cysteine methyl ester (500 mg, 1.21 mmol) in THF (10 mL) at roomtemperature and stirred until consumption of starting material wasobserved by HPLC. After conversion to the imidazole urea was complete,sarcosine hydrochloride (201 mg, 1.44 mmol) was added to the reactionmixture, followed by N,N-diisopropylethylamine (0.418 mL, 2.4 mmol) atroom temperature. The reaction mixture was heated at 50° C. andmonitored by HPLC for consumption of the imidazole urea. Afterdisappearance of the imidazole urea was observed, 0.552 mL of a 1Mlithium hydroxide solution was added to the reaction mixture and stirredat room temperature. When hydrolysis of the bis-ester was complete byHPLC, the reaction mixture was partitioned between ethyl acetate and a10% citric acid solution. The organic layer was washed with brine anddried over magnesium sulfate. The ethyl acetate was filtered andconcentrated to dryness. The crude product was purified by flashchromatography using ethyl acetate/hexanes as the eluent to give 74 mgof the product as a white waxy solid in 78% yield. ¹H NMR (500 MHz,Methanol-d4) δ 5.29-5.20 (m, 1H), 4.49 (dd, J=8.1, 4.9 Hz, 1H),4.15-4.02 (m, 2H), 3.33-3.24 (m, 2H), 3.21-3.14 (m, 1H), 3.04 (s, 3H),3.03-2.99 (m, 1H), 2.86 (dd, J=14.0, 8.1, 1.0 Hz, 1H), 2.05-2.00 (m,2H), 1.70 (d, J=1.4 Hz, 3H), 1.60-1.54 (m, 1H), 1.52-1.04 (m, 19H),0.95-0.82 (m, 12H). This compound corresponds to Compound C.

Example 14 Synthesis of(2S)-1-{[(1R)-1-carboxy-2-{[(2E)-3,7,11,15-tetramethylhexadec-2-en-1-yl]sulfanyl}ethyl]carbamoyl}pyrrolidine-2-carboxylicacid

The title compound was prepared according to the procedure for Example13 to give 216 mg of an off-white solid in 33% yield. The titledcompound was characterized as follows: ¹H NMR (501 MHz, Chloroform-d) δ8.82 (s, 2H), 5.61-5.44 (m, 1H), 5.21 (t, 1H), 4.67-4.43 (m, 2H),3.60-3.33 (m, 2H), 3.28-3.13 (m, 2H), 3.07-2.90 (m, 2H), 2.43-1.92 (m,6H), 1.66 (s, 3H), 1.54 (dp, J=13.3, 6.7 Hz, 1H), 1.47-1.01 (m, 19H),0.95-0.78 (m, 12H).

Example 15 Synthesis of(2R)-2-{[(carboxymethyl)(ethyl)carbamoyl]amino}-3-{[(2E)-3,7,11,15-tetramethyl-hexadec-2-en-1-yl]sulfanyl}propanoicacid

The title compound was prepared according to the procedure for Example13 to give 335 mg of a light yellow oil in 49% yield. ¹H NMR (501 MHz,Chloroform-d) δ 7.85 (s, 2H), 5.72 (d, J=7.0 Hz, 1H), 5.20 (t, J=7.7 Hz,1H), 4.59 (d, J=6.0 Hz, 1H), 4.18-3.91 (m, 2H), 3.37 (d, J=7.5 Hz, 2H),3.20 (qd, J=13.0, 7.8 Hz, 2H), 2.98 (qd, J=13.8, 5.6 Hz, 3H), 2.04-1.91(m, 2H), 1.65 (s, 3H), 1.53 (hept, J=6.6 Hz, 1H), 1.46-1.00 (m, 19H),0.91-0.81 (m, 12H).

Example 16 Synthesis of(2R)-2-{[bis(carboxymethyl)carbamoyl]amino}-3-{[(2E)-3,7,11,15-tetramethylhexadec-2-en-1-yl]sulfanyl}propanoicacid

The title compound was prepared according to the procedure for Example13 to give 407 mg of a foamy yellow solid in 60% yield. ¹H NMR (500 MHz,Methanol-d4) δ 5.27-5.19 (m, 1H), 4.47 (dd, J=7.8, 5.0 Hz, 1H),4.21-4.10 (m, 4H), 3.28 (dd, J=13.3, 8.2 Hz, 1H), 3.16 (dd, J=13.2, 7.3Hz, 1H), 2.98 (dd, J=13.9, 5.0 Hz, 1H), 2.83 (ddd, J=13.9, 7.8, 1.2 Hz,1H), 2.04 (td, J=7.2, 3.0 Hz, 2H), 1.70 (s, 3H), 1.55 (dq, J=13.3, 6.7Hz, 1H), 1.51-1.06 (m, 19H), 0.93-0.81 (m, 12H).

Example 17 Synthesis of disodium1-{[(1R)-1-carboxylato-2-{[(2E)-3,7,11,15-tetramethylhexa-dec-2-en-1-yl]sulfanyl}ethyl]carbamoyl}piperidine-4-carboxylate

The title compound was prepared according to the procedure for Example13 to give 175 mg of the carboxylic acid. The isolated carboxylic acidwas dissolved in 2 mL of ethanol, followed by addition of 0.062 mL of10N sodium hydroxide solution at room temperature, and stirred for 1hour. The resulting suspension was triturated with 2 mL of acetonitrile,filtered and washed with acetonitrile to give 120 mg of a white solid in17% yield. ¹H NMR (501 MHz, Deuterium Oxide) δ 5.18-5.04 (m, 1H), 4.14(dd, J=7.8, 4.9 Hz, 1H), 3.98 (d, J=12.3 Hz, 1H), 3.75 (d, J=12.6 Hz,1H), 3.19-3.03 (m, 2H), 2.89-2.60 (m, 4H), 2.30-2.16 (m, 1H), 1.97-1.82(m, 2H), 1.82-1.69 (m, 2H), 1.57 (s, 3H), 1.53-0.91 (m, 20H), 0.78 (d,J=6.1 Hz, 12H).

Example 18 Synthesis of disodium(2S,4R)-1-{[(1R)-1-carboxylato-2-{[(2E)-3,7,11,15-tetramethylhexadec-2-en-1-yl]sulfanyl}ethyl]carbamoyl}-4-hydroxypyrrolidine-2-carboxylate

The title compound was prepared according to the procedure for Example13 to give 200 mg of an off-white solid in 33% yield. ¹H NMR (500 MHz,Deuterium Oxide) δ 4.94-4.78 (m, 1H), 4.23-4.00 (m, 1H), 3.99-3.86 (m,1H), 3.48-3.02 (m, 2H), 3.02-2.68 (m, 3H), 2.76-2.39 (m, 2H), 2.01-1.80(m, 2H), 1.79-1.53 (m, 2H), 1.40-1.21 (m, 3H), 1.21-0.64 (m, 20H), 0.52(d, J=6.5 Hz, 12H).

Example 19 Synthesis of(2R)-2-{[(E)-piperidine-1-carbonyl]amino}-3-{[(2E)-3,7,11,15-tetramethylhexadec-2-en-1-yl]sulfanyl}propanoicacid

The title compound was prepared according to the procedure for Example13 to give 200 mg of a light brown oil in 18% yield. ¹H NMR (501 MHz,Methanol-d4) δ 6.73 (ddt, J=7.8, 6.5, 1.3 Hz, 1H), 5.90 (dd, J=6.8, 4.5Hz, 1H), 4.90 (dtd, J=13.3, 8.0, 5.4 Hz, 4H), 4.71 (qd, J=13.0, 7.8 Hz,2H), 4.50 (dd, J=13.6, 4.6 Hz, 1H), 4.38 (dd, J=13.6, 6.7 Hz, 1H),3.55-3.48 (m, 2H), 3.17 (s, 3H), 3.15-2.99 (m, 5H), 2.98-2.52 (m, 21H),2.44-2.31 (m, 12H).

Example 20 Synthesis of disodium1-{[(1R)-1-carboxylato-2-{[(2E)-3,7,11,15-tetramethylhexadec-2-en-1-yl]sulfanyl}ethyl]carbamoyl}piperidine-3-carboxylate

The title compound was prepared according to the procedure for Example13 to give 523 mg of an off-white solid in 39% yield. ¹H NMR (501 MHz,Deuterium Oxide) δ 5.19-5.06 (m, 1H), 4.17-4.03 (m, 1H), 3.93-3.76 (m,2H), 3.65-3.30 (m, 2H), 3.21-2.65 (m, 4H), 2.29-2.10 (m, 2H), 1.99-1.83(m, 4H), 1.57 (s, 3H), 1.47-1.39 (m, 1H), 1.39-0.92 (m, 19H), 0.90-0.65(m, 12H).

Example 21 Synthesis of(2R)-2-[(pyrimidin-2-yl)amino]-3-{[(2E)-3,7,11,15-tetramethylhexadec-2-en-1-yl]sulfanyl}propanoicacid

2-chloropyrimidine (127 mg, 1.11 mmol) was added at room temperature toa stirring solution of phytyl cysteine hydrochloride (500 mg, 1.11 mmol)in isopropanol (5 mL), followed by addition of 1 mL of a saturatedsodium bicarbonate solution. The reaction was heated at 110° C. in asealed tube for 3 days. Once the starting material was consumed by HPLC,the reaction mixture was cooled to room temperature, followed byaddition of 3 mL of a 1N LiOH solution. The reaction mixture was stirredovernight, then diluted in ethyl acetate and washed once with a 10%citric acid solution, once with brine and then dried over magnesiumsulfate. The ethyl acetate solution was filtered and concentrated on arotary evaporator to give the crude product as a brown oil. The oil waspurified by flash chromatography using ethyl acetate in hexanes as theeluent to give 173 mg of the product as a white solid in 32% yield. Thetitled compound was characterized as follows: ¹H NMR (501 MHz,Methanol-d4) δ 8.29 (d, J=4.8 Hz, 2H), 6.66 (t, J=4.9 Hz, 1H), 5.20 (td,J=7.9, 1.7 Hz, 1H), 4.77-4.70 (m, 1H), 3.20 (tt, J=13.2, 6.4 Hz, 2H),3.14-3.05 (m, 1H), 3.00 (dd, J=13.8, 6.4 Hz, 1H), 2.03-1.94 (m, 2H),1.61 (s, 3H), 1.52 (dq, J=13.3, 6.6 Hz, 1H), 1.45-0.98 (m, 19H),0.94-0.77 (m, 12H).

Example 22 Synthesis of2-{[(1R)-1-carboxy-2-{[(2E)-3,7,11,15-tetramethylhexadec-2-en-1-yl]-sulfanyl}ethyl]amino}pyrimidine-4-carboxylicacid

The title compound was prepared according to the procedure for Example21 to give 486 mg of a white solid in 83% yield. ¹H NMR (501 MHz,Methanol-d4) δ 8.49 (d, J=4.9 Hz, 1H), 7.27 (d, J=4.9 Hz, 1H), 5.18 (t,J=7.7 Hz, 1H), 4.86 (s, 1H), 3.25-3.13 (m, 2H), 3.12-3.04 (m, 1H),3.02-2.93 (m, 1H), 2.04-1.85 (m, 2H), 1.58 (s, 3H), 1.49 (dt, J=13.3,6.6 Hz, 1H), 1.42-0.95 (m, 19H), 0.87-0.77 (m, 12H).

Example 23 Synthesis of2-{[(1R)-1-carboxy-2-{[(2E)-3,7,11,15-tetramethylhexadec-2-en-1-yl]sulfanyl}ethyl]amino}pyrimidine-5-carboxylicacid

The title compound was prepared according to the procedure for Example21 to give 497 mg of a white solid in 85% yield. ¹H NMR (501 MHz,Methanol-d4) δ 8.84 (d, J=7.5 Hz, 2H), 5.22 (t, J=7.5 Hz, 1H), 4.90-4.87(m, 1H), 3.28 (dd, J=13.4, 8.0 Hz, 1H), 3.20 (dd, J=13.3, 7.4 Hz, 1H),3.16-3.09 (m, 1H), 2.97 (dd, J=14.0, 7.8 Hz, 1H), 2.01 (t, J=7.4 Hz,2H), 1.66 (d, J=1.3 Hz, 3H), 1.55 (dt, J=13.3, 6.7 Hz, 1H), 1.47-1.04(m, 19H), 0.96-0.83 (m, 12H).

Example 24 Synthesis of(2R)-2-{[(carboxymethyl)(methyl)carbamoyl]amino}-3-{[(2Z)-3,7,11,15-tetramethylhexadec-2-en-1-yl]sulfanyl}propanoicacid

Disodium (2R)-2-{[(carboxylatomethyl)(methyl)carbamoyl]amino}-3-{[(2E)-3,7,11,15-tetramethylhexadec-2-en-1-yl]sulfanyl}propanoate(5.0 g, 8.94 mmol) was dissolved in 10 mL of water, followed by additionof sodium sulfite (7.07 g, 44.7 mmol) at room temperature. The solutionwas heated at 80° C. for 72 hours, then cooled to room temperature. Thecrude reaction was extracted 1× with ethyl acetate. The aqueous layerwas acidified with a 10% citric acid solution to give a suspension whichwas extracted 3×'s with 25 mL portions of ethyl acetate. The combinedorganic layers were washed with brine, dried over magnesium sulfate, andthe ethyl acetate solution was filtered and concentrated on a rotaryevaporator to give the crude product as an orange solid. The crudeproduct was cleaned up by flash chromatography using ethyl acetate inhexanes as the eluent to give a 5:1 mixture of trans:cis isomers. Theisomers were separated on preparative HPLC to give 70 mg of the productas a white waxy solid in 2% yield. ¹H NMR (500 MHz, Methanol-d4) δ 5.26(td, J=7.9, 1.6 Hz, 1H), 4.48 (dd, J=7.8, 4.9 Hz, 1H), 4.08 (d, J=1.3Hz, 2H), 3.29-3.18 (m, 2H), 3.04 (s, 3H), 3.02-2.99 (m, 1H), 2.89 (dd,J=13.8, 7.8 Hz, 1H), 2.14-2.06 (m, 2H), 1.75 (d, J=1.4 Hz, 3H), 1.55(dq, J=13.4, 6.7 Hz, 1H), 1.50-1.06 (m, 19H), 0.98-0.83 (m, 12H). Thiscompound corresponds to Compound BI.

Example 25 Synthesis of(2S)-1-{[(1R)-1-carboxy-2-{[(2E,6E)-3,7,11-trimethyldodeca-2,6,10-trien-1-yl]sulfanyl}ethyl]carbamoyl}pyrrolidine-2-carboxylicacid

Step 1: Synthesis of N-(cyanomethyl)glycine amide

Bromoacetonitrile (0.779 mL, 14.8 mmol) was added to a slurry ofglycinamide (1 g, 13.5 mmol) and sodium bicarbonate (2.03 g, 24.2 mmol)in 20 mL of acetonitrile at room temperature. The reaction was heated at60° C. for 6 hours and monitored by TLC. After no starting materialremained, the crude reaction was cooled to room temperature, filteredand concentrated to give the product as a yellow solid. The solid wascarried onto the next step without further purification.

Step 2: Synthesis of(2S)-1-{[(1R)-1-carboxy-2-{[(2E,6E)-3,7,11-trimethyldodeca-2,6,10-trien-1-yl]sulfanyl}ethyl]carbamoyl}pyrrolidine-2-carboxylicacid

The title compound was prepared according to the procedure for Examples1-5 to give 8 mg of tan solid in 1% yield. ¹H NMR (500 MHz, Methanol-d4)δ 5.22 (t, J=7.8 Hz, 1H), 4.65 (dd, J=11.8, 4.5 Hz, 1H), 4.11 (ddd,J=17.0, 14.4, 8.1 Hz, 4H), 3.28-3.08 (m, 4H), 2.02-1.96 (m, 2H), 1.68(d, J=4.0 Hz, 3H), 1.58-1.49 (m, 1H), 1.48-1.02 (m, 19H), 0.93-0.79 (m,12H).

Example 26 Synthesis of5-{[(1R)-1-carboxy-2-{[(2E)-3,7,11,15-tetramethylhexadec-2-en-1-yl]sulfanyl}ethyl]amino}pyrazine-2-carboxylicacid

Phytyl cysteine methyl ester (500 mg, 1.21 mmol), 2-Pyrazinecarboxylicacid-5-chloro-ethyl ester (208 mg, 1.21 mmol) andN,N-diisopropylethylamine (0.421 mL, 2.42 mmol) were dissolved in 5 mLof dioxane and heated at 120° C. in a sealed tube for 72 hours. Thereaction mixture was cooled to room temperature, diluted withtetrahydrofuran and washed once with brine. 1N lithium hydroxidesolution (3.6 mL) was added to the reaction mixture and stirred at roomtemperature overnight. The crude reaction was diluted with ethyl acetateand washed successively with a 10% citric acid solution and brine. Themixture was dried over magnesium sulfate, filtered, and concentrated ona rotary evaporator to give the crude product as an orange solid whichwas purified by flash chromatography using ethyl acetate in hexanes togive 91 mg of the product as a pale yellow solid in 14% yield. ¹H NMR(500 MHz, Methanol-d4) δ 10.19 (d, J=1.4 Hz, 1H), 9.56 (d, J=1.3 Hz,1H), 6.75-6.66 (m, 1H), 6.38-6.31 (m, 1H), 4.76 (dd, J=13.4, 8.0 Hz,1H), 4.69 (dd, J=13.6, 7.6 Hz, 1H), 4.60 (dd, J=13.9, 4.7 Hz, 1H), 4.40(dd, J=14.0, 8.1 Hz, 1H), 3.49 (t, J=7.4 Hz, 2H), 3.15 (s, 3H), 3.03(hept, J=6.6 Hz, 1H), 2.96-2.51 (m, 12H), 2.42-2.30 (m, 12H).

Example 27 Synthesis of2-{[(1R)-1-carboxy-2-{[(2E)-3,7,11,15-tetramethylhexadec-2-en-1-yl]sulfanyl}ethyl]amino}-4-methylpyrimidine-5-carboxylicacid

The title compound was prepared according to the procedure for Example26 to give 250 mg of a white solid in 38% yield. ¹H NMR (500 MHz,Methanol-d4) δ 8.81 (d, J=14.4 Hz, 1H), 5.26-5.16 (m, 1H), 4.92-4.85 (m,1H), 3.28 (dd, J=13.4, 8.1 Hz, 1H), 3.20 (dd, J=13.4, 7.5 Hz, 1H), 3.12(dd, J=14.0, 4.7 Hz, 1H), 3.02-2.90 (m, 1H), 2.67 (s, 3H), 2.03-1.97 (m,2H), 1.66 (s, 3H), 1.54 (dq, J=13.3, 6.6 Hz, 1H), 1.49-1.03 (m, 19H),0.94-0.80 (m, 12H).

Example 28 Synthesis of(2R)-2-({2-[(carboxymethyl)(methyl)amino]pyrimidin-4-yl}amino)-3-{[(2E)-3,7,11,15-tetramethylhexadec-2-en-1-yl]sulfanyl}propanoicacid

Step 1: Synthesis of methyl(2R)-2-[(2-chloropyrimidin-4-yl)amino]-3-{[(2E)-3,7,11,15-tetramethylhexadec-2-en-1-yl]sulfanyl}propanoate

2,4-Dichloropyrimidine (270 mg, 1.81 mmol) was added to a solution ofphytyl cysteine methyl ester (750 mng, 1.81 mmol) andN,N-diisopropylethylamine (630 mL, 3.62 mmol) in tetrahydrofuran (10 mL)that was cooled in an ice/water bath. The reaction was heated at 110° C.in a sealed tube overnight and monitored by HPLC. The HPLC indicated a4:1 mixture of regioisomers. The reaction mixture was cooled to roomtemperature, concentrated on a rotary evaporator, and the crude yellowoil was purified by flash chromatography using ethyl acetate in hexanesas the eluent to give 557 mg of the product in 58% yield. ¹H NMR (500MHz, Methanol-d4) δ 7.94 (d, J=6.0 Hz, 1H), 6.58 (d, J=6.0 Hz, 1H),5.29-5.10 (m, 1H), 4.95 (t, J=6.7 Hz, 1H), 3.77 (s, 3H), 3.29 (dd,J=13.4, 8.2 Hz, 1H), 3.19 (dd, J=13.5, 7.7 Hz, 1H), 3.04 (dd, J=14.0,5.1 Hz, 1H), 2.93-2.59 (m, 1H), 2.08-2.03 (m, 2H), 1.69 (s, 3H),1.59-1.51 (m, 1H), 1.51-1.04 (m, 19H), 0.97-0.84 (m, 12H).

Step 2: Synthesis of(2R)-2-({2-[(carboxymethyl)(methyl)amino]pyrimidin-4-yl}amino)-3-{[(2E)-3,7,11,15-tetramethylhexadec-2-en-1-yl]sulfanyl}propanoicacid

Methyl(2R)-2-[(2-chloropyrimidin-4-yl)amino]-3-{[(2E)-3,7,11,15-tetramethylhexadec-2-en-1-yl]sulfanyl}propanoate(500 mg, 0.950 mmol), sarcosine methyl ester hydrochloride (398 mg, 2.85mmol) and N,N-diisopropylethylamine (0.827 mL, 4.75 mmol) were combinedin a sealed tube and heated at 120° C. for 2 hours. The reaction mix wasdiluted in tetrahydrofuran and washed once with brine. The organic layerthen had 1M lithium hydroxide solution (2.85 mL) added and the reactionmixture was stirred at room temperature overnight. The reaction mixtureis diluted with ethyl acetate, washed with 10% w/v citric acid solution,then brine and dried over magnesium sulfate. The ethyl acetate isfiltered and concentrated on a rotary evaporator to give the crudeproduct as a yellow oil that is purified by flash chromatography usingethyl acetate in hexanes as the eluent to give 320 mg of the product asa white solid in 59% yield. ¹H NMR (500 MHz, Deuterium Oxide) δ 7.51 (s,2H), 6.05 (s, 1H), 5.07 (s, 1H), 3.79-3.41 (m, 2H), 3.26-2.75 (m, 7H),1.79 (s, 2H), 1.54 (d, J=41.6 Hz, 3H), 1.44-0.80 (m, 19H), 0.71 (d,J=9.2 Hz, 12H).

Example 29 Synthesis of(2R)-2-({4-[(carboxymethyl)(methyl)amino]pyrimidin-2-yl}amino)-3-{[(2E)-3,7,11,15-tetramethylhexadec-2-en-1-yl]sulfanyl}propanoicacid

Step 1: Synthesis of methyl(2R)-2-[(4-chloropyrimidin-2-yl)amino]-3-{[(2E)-3,7,11,15-tetramethylhexadec-2-en-1-yl]sulfanyl}propanoate

The title compound was prepared according to the procedure for Example28, Step 1 to give 169 mg of product in 17% yield. ¹H NMR (500 MHz,Chloroform-d) δ 8.16 (d, J=5.1 Hz, 1H), 6.68-6.59 (m, 1H), 5.19 (t,J=7.8 Hz, 1H), 4.86 (d, J=5.8 Hz, 1H), 3.77 (d, J=5.5 Hz, 3H), 3.25-3.08(m, 2H), 3.08-2.99 (m, 1H), 2.95 (dd, J=13.8, 6.5 Hz, 1H), 2.04-1.90 (m,2H), 1.62 (d, J=5.3 Hz, 3H), 1.55-1.46 (m, 1H), 1.44-0.99 (m, 19H), 0.86(dd, J=10.7, 6.5 Hz, 12H).

Step 2: Synthesis of(2R)-2-({4-[(carboxymethyl)(methyl)amino]pyrimidin-2-yl}amino)-3-{[(2E)-3,7,11,15-tetramethylhexadec-2-en-1-yl]sulfanyl}propanoicacid

The title compound was prepared according to the procedure for Example28, Step 2 to give 13 mg of product in 9% yield. ¹H NMR (500 MHz,Methylene Chloride-d2) δ 7.58 (s, 1H), 7.25 (s, 1H), 6.36-5.89 (m, 1H),5.15-4.91 (m, 1H), 4.41-4.06 (m, 2H), 3.63-3.06 (m, 7H), 1.93 (d, J=42.5Hz, 2H), 1.58 (d, J=48.8 Hz, 3H), 1.47-0.86 (m, 20H), 0.80-0.64 (m,12H).

Example 30 Synthesis of(2R)-2-amino-3-methyl-3-{[(2E)-3,7,11,15-tetramethylhexadec-2-en-1-yl]sulfanyl}butanoicacid

The title compound was prepared according to the phytyl cysteineprocedure to give 2.4 g of a yellow solid in 83% yield. ¹H NMR (500 MHz,Chloroform-d) δ 5.42 (tq, J=6.2, 1.0 Hz, 1H), 3.81 (s, 1H), 3.15 (ddq,J=12.5, 6.2, 1.0 Hz, 1H), 3.10-3.02 (m, 1H), 2.00 (td, J=7.1, 1.1 Hz,2H), 1.72 (s, 3H), 1.65-1.54 (m, 1H), 1.54-1.12 (m, 25H), 0.93-0.70 (m,12H).

Example 31 Synthesis of disodium(2R)-2-(3-carboxylatopropanamido)-3-methyl-3-{[(2E)-3,7,11,15-tetramethylhexadec-2-en-1-yl]sulfanyl}butanoate

Succinic anhydride (233 mg, 2.33 mmol) was added to a stirringsuspension of(2R)-2-amino-3-methyl-3-{[(2E)-3,7,11,15-tetramethylhexadec-2-en-1-yl]sulfanyl}butanoic acid (1 g, 2.33 mmol) in 10 mL of a 9:1 ethanol:watermixture at room temperature and heated at 60° C. overnight. The reactionwas cooled to room temperature, concentrated on a rotary evaporator,diluted in ethyl acetate and washed successively with 10% w/v citricacid solution and brine. The ethyl acetate was dried over magnesiumsulfate, filtered and concentrated on a rotary evaporator to give thecrude product as a yellow oil that was purified by flash chromatographyusing ethyl acetate in hexanes as the eluent to give the carboxylicacid. The purified carboxylic acid was dissolved in 10 mL of ethanol and21% sodium ethoxide solution in ethanol was slowly added to the solutionuntil the pH registered 9. The resulting ethanolic suspension wascentrifuged at 2000 rpm for 2 minutes. The ethanol was decanted and theethanol wash was repeated twice more. Acetonitrile was then substitutedfor ethanol and the wash was repeated three times. The resulting solidwas dried on a rotary evaporator to give 121 mg of a white solid in 9%yield. ¹H NMR (500 MHz, Deuterium Oxide) δ 5.11 (t, J=8.0 Hz, 1H), 4.13(s, 1H), 3.15-3.03 (m, 2H), 2.61-2.27 (m, 4H), 1.99-1.79 (m, 2H), 1.57(s, 3H), 1.50-1.39 (m, 1H), 1.39-0.95 (m, 25H), 0.79 (d, J=6.2 Hz, 12H).

Example 32 Synthesis of disodium2-{[(1R)-1-carboxylato-2-methyl-2-{[(2E)-3,7,11,15-tetramethylhexadec-2-en-1-yl]sulfanyl}propyl]amino}pyrimidine-5-carboxylate

2-Chloropyrimidine-5-carboxylic acid methyl ester (434 mg, 2.33 mmol)was added to a stirring suspension of(2R)-2-amino-3-methyl-3-{[(2E)-3,7,11,15-tetramethylhexadec-2-en-1-yl]sulfanyl}butanoicacid (1 g, 2.33 mmol) and N,N-diisopropylethylamine (1.21 mL, 6.99 mmol)in dioxane (10 mL) at room temperature and heated to 60° C. overnight.The reaction mixture is cooled to room temperature and washed once withbrine. The reaction mixture is diluted with an additional 5 mL ofdioxane, followed by addition of 1M lithium hydroxide (10 mL) at roomtemperature and stirred overnight. The reaction mixture is diluted withethyl acetate, washed with 10% w/v citric acid solution, then brine anddried over magnesium sulfate. The ethyl acetate is filtered andconcentrated on a rotary evaporator to give the crude product as ayellow oil that is purified by flash chromatography using ethyl acetatein hexanes as the eluent to give the purified carboxylic acid as anoff-white solid. The carboxylic acid was dissolved in ethanol, thensolid sodium ethoxide was added until the pH reached 9. The resultingethanolic suspension was centrifuged at 2000 rpm for 2 minutes. Theethanol was decanted and the ethanol wash was repeated twice more.Acetonitrile was then substituted for ethanol and the wash was repeatedthree times. The resulting solid was dried on a rotary evaporator togive 165 mg of a white solid in 12% yield. ¹H NMR (500 MHz, DeuteriumOxide) δ 8.61 (s, 2H), 5.07 (s, 1H), 4.21 (s, 1H), 3.17-3.02 (m, 2H),1.92-1.74 (m, 2H), 1.49 (d, J=6.4 Hz, 3H), 1.44-0.82 (m, 26H), 0.79-0.64(m, 12H).

Example 33 Synthesis of trisodium(2R)-2-{[bis(carboxylatomethyl)carbamoyl]amino}-3-{[(2E,6E)-3,7,11-trimethyldodeca-2,6,10-trien-1-yl]sulfanyl}propanoate

The title compound was prepared according to the procedure for Examples1-5 to give the carboxylic acid. The isolated carboxylic acid was thendissolved in 10 mL of ethanol and enough solid sodium ethoxide was addedto bring the pH of the mixture to 7. The resulting ethanolic suspensionwas centrifuged at 2000 rpm for 2 minutes. The ethanol was decanted andthe ethanol wash was repeated twice more. Acetonitrile was thensubstituted for ethanol and the wash was repeated three times. Theresulting solid was dried on a rotary evaporator to give 613 mg of awhite solid in 75% yield. ¹H NMR (500 MHz, Deuterium Oxide) δ 5.19 (td,J=8.0, 4.1 Hz, 1H), 5.15-5.05 (m, 2H), 4.13 (dd, J=7.4, 4.6 Hz, 1H),3.84 (d, J=18.0 Hz, 2H), 3.70 (d, J=18.0 Hz, 2H), 3.13 (tt, J=13.1, 6.4Hz, 2H), 2.87 (dd, J=13.6, 4.7 Hz, 1H), 2.75 (ddd, J=13.7, 7.4, 2.7 Hz,1H), 2.11-1.88 (m, 8H), 1.67-1.48 (m, 12H).

Example 34 Synthesis of(2S)-1-{[(1R)-1-carboxy-2-{[(2E,6E)-3,7,11-trimethyldodeca-2,6,10-trien-1-yl]sulfanyl}ethyl]carbamoyl}pyrrolidine-2-carboxylicacid

The title compound was prepared according to the above-describedprocedures to give 209 mg of tan solid in 30% yield. ¹H NMR (500 MHz,Methanol-d4) δ 5.24 (q, J=7.8 Hz, 1H), 5.19-5.07 (m, 2H), 4.54-4.48 (m,1H), 4.41 (ddd, J=11.2, 8.5, 2.5 Hz, 1H), 3.63-3.42 (m, 2H), 3.28 (ddd,J=13.8, 8.3, 6.0 Hz, 1H), 3.23-3.08 (m, 1H), 3.01 (dt, J=14.0, 4.9 Hz,1H), 2.85 (ddd, J=21.0, 13.9, 7.9 Hz, 1H), 2.29-1.94 (m, 12H), 1.82-1.57(m, 12H).

Example 35 Synthesis of(2R)-2-[2-(carboxymethoxy)acetamido]-3-{[(2E,6E)-3,7,11-trimethyldodeca-2,6,10-trien-1-yl]sulfanyl}propanoicacid

The title compound was prepared according to the above-describedprocedures to give 250 mg of light brown oil in 50% yield. ¹H NMR (500MHz, Methanol-d4) δ 5.25 (q, J=8.3 Hz, 1H), 5.20-5.06 (m, 2H), 4.68 (dd,J=8.4, 4.6 Hz, 1H), 4.27-4.15 (m, 4H), 3.31-3.14 (m, 2H), 3.06 (ddd,J=14.0, 4.6, 2.6 Hz, 1H), 2.92-2.80 (m, 1H), 2.22-1.95 (m, 8H),1.79-1.59 (m, 12H).

Biological Examples

Described below are in vivo assays used to measure the biologicalactivity of provided compounds, including the anti-inflammatory orproinflammatory properties of the compounds, as measured by edemainhibition, erythema inhibition and MPO inhibition.

Example A Antimicrobial Assays

To determine minimal inhibitory concentration (MIC), reagents weredissolved in vehicle (5% v/v) and then added to bacteria suspension. P.acnes (ATCC® 6919™) at 10⁶ CFU/mL was incubated with test materials atthe concentrations of two-fold serial dilution (0.25-500 μg/mL) andincubated for 72 hours (P. acnes). To determine minimal bactericidalconcentration (MBC) against P. acnes, bacteria (107 CFU/mL) wasincubated with reagents at various concentrations (12.5-100 μg/mL inPBS) under anaerobic conditions. Cultures were diluted 1:10-1:10⁶ withPBS, and MBC was determined by spotting the dilution (5 mL) on aBrucella broth agar plate to count colony-forming units (CFUs).

The following results were obtained:

P. acnes Compound MIC MBC Tested (μg/mL) (μg/mL) A 10 J 32 K >250 B 24L >16 M 16 N >250 O 32 P 10 Q 125 C 6 22 R >25 D >250 T 22 F 6 I >16 E 57 G 4 1 U 19 H 6

P. acnes (ATCC® 6919™) was cultured as described above. Bacteriabiofilms were established by seeding P. acnes cultures in 96-well platesand incubating for 24 hours without agitation. Later, biofilms wereincubated with test materials for 24 hours. Remaining biofilms werewashed and stained with crystal violet. Staining solution was removed,wells rinsed with water and dye was extracted with 1% w/v SDS. Theabsorbance was measured at 595 nm in a microplate reader. MBEC wasdefined as the minimum concentration necessary to achieve ≥80%eradication of attached biofilm compared to vehicle-only control.Results from disk diffusion susceptibility testing (Kirby-Bauer Method)after 72 hours incubation were also obtained.

The following results were obtained:

Compound Tested MBEC - μg/mL (μM) C 9 E 12 (21) G 7 (11) BenzoylPeroxide 367 (1515) Salicylic Acid >8000 (>57920) Azelaic Acid 8000(42503) Clindamycin 0.6 (1)

Example B Gene Expression on Human Keratinocytes (AntimicrobialPeptides)

Normal human epidermal keratinocytes (NHEKs) from neonatal donors wereobtained from Thermo-Fisher (Cat No. C-001-5C). Cells were cultured in6-well plates for 24 hours before treatments with EpiLife media (Cat No.MEPI500CA) supplemented with keratinocytes growth supplement (Cat No.S0015). On Day 2, media was removed and incubated with test materials(10 μM) for 24 hours at 37° C. and 5% CO₂. On Day 3, total RNA wasextracted from cells using the RNAqueous® kit (Ambion®; Cat No. 1912)and cDNA was obtained using the High Capacity RNA-to-cDNA kit (AppliedBiosystems®; Cat No. 4387406). Quantitative PCR (qPCR) was performedusing the TaqMan® Fast Advanced Master Mix (Applied Biosystems®; Cat No.4444556) and specific TaqMan®-probes human gene primers DEFB4B (hBD2),DEFB103 (hBD3), HCAP18 and GAPDH to calculate the relative gene foldexpression change per treatment. Gene expression analysis was performedusing the the comparative Ct method (also known as the2-[delta][delta]Ct) approach by comparing the Ct values of the treatedsamples with the untreated samples and normalized to GAPDH geneexpression as endogenous housekeeping gene. Results were represented asfold-expression/untreated cells.

The following results were obtained:

NHEK-gene Expression hBD2 hBD3 hCAP18 Compound Fold- Testedexpression/untreated cells E 1.1 2.9 0.7 G 2.5 4.7 0.6 C 0.7 9.5 0.5Benzoyl Peroxide 1.6 1.2 2.8 Salicylic Acid 1.0 1.2 1.2 Azelaic Acid 1.80.9 1.1

Example C

P. acnes-Induced Pro-Inflammatory Cytokines on Human PBMCs

Cryopreserved human Peripheral Blood Mononuclear cells (PBMCs) fromhealthy adult donors were obtained from Zen Bio, Inc (Cat No.SER-PBMC-F). Cells were cultured in 12-well plates with lymphocyte media(Cat No. LYMPH-1) and incubated with test materials (30 μM) and live P.acnes (ATCC® 6919TM) at 1:1 PBMC: P. acnes bacteria ratio for 24 hoursat 37° C. and 5% CO₂. After incubation, cell media supernatants wereharvested and used to measure pro-inflammatory cytokine levels (IL-8,TNF-α, IL-1b, IL-17) using ELISA kits (BD Biosciences® #557966, #555212,#555244; R&D Systems® # DY317). Total RNA was extracted from cells usingthe RNAqueous® kit (Ambion®; Cat No. 1912) and cDNA was obtained usingthe High Capacity RNA-to-cDNA kit (Applied Biosystems®; Cat No.4387406). Quantitative PCR (qPCR) was performed using the TaqMan® FastAdvanced Master Mix (Applied Biosystems®; Cat No. 4444556) and specificTaqMan®-probes human gene primers CXCL8 (IL-8), IL1B (IL-1b), TNF(TNF-α), IL17A (IL-17A) and GAPDH to calculate the relative gene foldexpression change per treatment. Gene expression analysis was performedusing the comparative Ct method (also known as the 2-[delta][delta]Ct)approach by comparing the Ct values of P. acnes-only treated cells withthe untreated samples and normalized to GAPDH gene expression asendogenous housekeeping gene. Results were represented as percent ofinhibition relative to untreated and P. acnes-only treated cells.

The following results were obtained:

P. acnes-PBMCs IL-8 IL-1b IL-17 TNFa- Com- Pro- Pro- Pro- Pro- IL-8TNFa- IL-1b IL-17 pound tein tein tein tein Gene Gene Gene Gene Tested %inhibition A 38 32 Q 14 0 59 72 C 8 36 0 0 0 0 0 0 T 0 0 27 0 I 52 0 867 E 67 82 23 0 8 0 20 0 G 74 91 29 0 0 0 10 0 V 46 0 83 0 Clinda- 36 3289 10 0 10 3 41 mycin HCl Benzoyl 78 33 15 0 Peroxide Salicylic 0 40 0 0Acid Azelaic 43 66 0 0 Acid

Example D Peptidoglycan (PGN)-Induced Pro-Inflammatory Cytokines onNHEKs

Normal human epidermal keratinocytes (NHEKs) from neonatal donors wereobtained from Thermo-Fisher (Cat No. C-001-5C). Cells were cultured in96-well plates for 24 hours with EpiLife media (Cat No. MEPI500CA)supplemented with keratinocytes growth supplement (Cat No. S0015). OnDay 2, media was removed and replaced with supplement-depleted mediumfor 24 hours. On Day 3, media was removed and cells were pre-treatedwith test materials (≤1 μM) for 2 hours and later co-treated with testmaterials and PGN (Sigma Aldrich, Cat No. 77140) at 10 μg/mL andincubated for 24 hours at 37° C. and 5% CO₂. PGN is a TLR-2 agonist.After incubation, cell media supernatants were harvested and used tomeasure pro-inflammatory cytokine levels (IL-8) using ELISA kit (BDBiosciences® #555244). Results were represented as percent of inhibitionrelative to untreated and PGN-only treated cells. IC₅₀ values weredetermined by non-linear regression analysis using the four-parameterlogistic equation.

The following results were obtained:

PGN- NHEK IL-8 Compound Protein Tested IC50 (μM) C 0.25 E 0.25 G 0.05Benzoyl Peroxide >1 Salicylic Acid >1

Example E

S. aureus-Induced TSLP on NHEKs

Normal human epidermal keratinocytes (NHEKs) from neonatal donors wereobtained from Thermo-Fisher (Cat No. C-001-5C). Cells were cultured in96-well plates for 24 hours with EpiLife media (Cat No. MEPI500CA)supplemented with keratinocytes growth supplement (Cat No. S0015). OnDay 2, media was removed and replaced with supplement-depleted mediumfor 24 hours. On Day 3, media was removed and cells were pre-treatedwith test materials (≤30 μM) for 2 hours and later co-treated with testmaterials and live S. aureus (ATCC® 33591) at 1:1 NHEK: bacteria ratiofor 24 hours at 37° C. and 5% CO₂. After incubation, cell mediasupernatants were harvested and used to measure TSLP levels using ELISAkit (R&D Systems® # DY1398). Results were represented as percent ofinhibition relative to untreated and S. aureus-only treated cells. IC₅₀values were determined by non-linear regression analysis using thefour-parameter logistic equation.

The following results were obtained:

S. aureus- NHEK Compound TSLP Protein Tested IC50 (μM) A 9 C 3 T 10AN2728 (2%) 5

Example F T-Cell Receptor (TCR)-Induced, Lipoolysaccharide (LPS)-Inducedand Phytohemagglutinin (PHA)-Induced Cytokines on PBMCs

Cryopreserved human Peripheral Blood Mononuclear cells (PBMCs) fromhealthy adult donors were obtained from Zen Bio, Inc (Cat No.SER-PBMC-F). Cells were cultured in 96-well plates with lymphocyte media(Cat No. LYMPH-1) and were pre-treated with test materials (≤100 μM) for2 hours and later co-treated with test materials and anti-CD3/CD28 beads(Thermo-Fisher; Cat No. 11131D) at 1:0.4 PBMC: bead ratio for 24 hoursat 37° C. and 5% CO₂. After incubation, cell media supernatants wereharvested and used to measure cytokine levels (IL-4, IL-5, IL-10) usingELISA kits (BD Biosciences® #555194, #555157; R&D Systems® # DY317).Results were represented as percent of inhibition relative to untreatedand anti-CD3/CD28 beads-only treated cells. IC₅₀ values were determinedby non-linear regression analysis using the four-parameter logisticequation.

The following results were obtained:

TCR-PBMCs IL-4 IL-5 Protein Protein IL-10 Compound IC50 IC50 ProteinTested (μM) (μM) IC50 (μM) A >100 55 42 B 52 50 46 C 20 46 34D >100 >100 100 T 25 9 19 E 42 63 39 AN2728 2 1 9 (2%)

By a similar method, but instead of anti-CD3/CD28 beads (Thermo-Fisher;Cat No. 11131D), compounds A, C, T and E were treated with LPS (SigmaAldrich, Cat. No. LF4321) to measure inhibition of LPS-inducedcytokines, and compounds C and T were treated with PHA-L (Sigma Aldrich,Cat No. 11249738001) to measure inhibition of PHA-induced cytokines.These compounds did not show significant inhibition as compared tocontrols.

Example G Nickel (Ni²⁺)-Induced Cytokines on HDMECs

Human Dermal Microvascular Endothelial cells (HDMECs) from human skintissues were obtained from Sciencell, Inc. (Cat No. 2000). Cells werecultured in 96-well plates for 24 hours with ECM media (Cat No. 1001)supplemented with endothelial cell growth supplement (Cat No. S0015) and5% v/v FBS. On Day 2, media was removed and replaced withsupplement-depleted medium for 24 hours. On Day 3, media was removed andcells were pre-treated with test materials (≤10 μM) for 2 hours andlater co-treated with test materials and 1 mM NiSO₄ (Sigma-Aldrich, CatNo. 227676) for 6 hours at 37° C. and 5% CO₂. After incubation, cellmedia supernatants were harvested and used to measure IL-6 levels usingELISA kit (BD Biosciences® #555220). Results were represented as percentof inhibition relative to untreated and NiSO₄-only treated cells. IC₅₀values were determined by non-linear regression analysis using thefour-parameter logistic equation.

The following results were obtained:

Nickel- HDMECs IL-6 Protein Compound IC50 Tested (μM) A 0.03 C 0.02 T0.01 AN2728 100 (2%)

Example H TPA-Induced Pro-Inflammatory Cytokines on NHEKs

Normal human epidermal keratinocytes (NHEKs) from neonatal donors wereobtained from Thermo-Fisher (Cat No. C-001-5C). Cells were cultured in96-well plates for 24 hours with EpiLife media (Cat No. MEPI500CA)supplemented with keratinocytes growth supplement (Cat No. S0015). OnDay 2, media was removed and replaced with supplement-depleted mediumfor 24 hours. On Day 3, media was removed and cells were pre-treatedwith test materials (≤1 μM) for 2 hours and later co-treated with testmaterials and TPA (Sigma Aldrich, Cat No. P8139) at 5 ng/mL andincubated for 24 hours at 37° C. and 5% CO₂. After incubation, cellmedia supernatants were harvested and used to measure pro-inflammatorycytokine levels (IL-8) using ELISA kit (BD Biosciences® #555244).Results were represented as percent of inhibition relative to untreatedand TPA-only treated cells. IC₅₀ values were determined by non-linearregression analysis using the four-parameter logistic equation.

The following results were obtained:

TPA-NHEK IC₅₀ (μM) Compound Tested IL-8 C 0.02 T 0.03 AN2728 0.02 FK5060.01

Example I TPA-Induced Skin Irritation In Vivo Model

Outbred male Swiss Webster (ICR) mice were purchased from Hilltop LabAnimals (Scottdale, Pa.) and were used between 10 and 12 weeks of ageand we followed a similar protocol previously described (Gordon et al.,2008). Mice received 1.2 μg/20 μl TPA dissolved in acetone (10 μlapplied both to the dorsal and ventral surfaces of the mouse ear using asolvent pipette) to each ear to induce acute irritation (6 per group).Test Materials were co-treated with TPA or applied 5 minutes after TPAdose, at various concentrations (0.6 to 800 μg/20 μl) in ethanol. After24 hour treatment, edema was measured by ear thickness.

The following results were obtained:

TPA Ear model @ 1% w/v Compound Edema % Tested inhibition MPO %inhibition A 50 C 64 88 T 61 83 FK506 0 81 AN2728 (2%) 43

Example J Oxazolone-Induced Delayed-Type Hypersensitivity (DTH) In VivoModel

Inbred male Balb/C mice were purchased from Hilltop Lab Animals(Scottdale, Pa.) and were used between 8 and 10 weeks of age. Mice backswere shaved and 100 μl of 3% v/v Oxazolone (Sigma Aldrich, Cat No.E0753) in acetone/olive oil (4:1) was applied to dorsal skin forsensitization. On Day 7, ears were challenged with 0.5% v/v Ozaxoloneand 30 minutes after challenge, test materials at 3% w/v were applied toears (10 μl applied both to the dorsal and ventral surfaces of the mouseear using a solvent pipette) and 24 hours later, skin thickness (edema)was measured. A 6-mm punch biopsy was obtained from each ear, snapfrozen in liquid nitrogen. Ear skin biopsy punches were pulverized usingFastPrep®-24 Biopulverizer (MP Biomedical, CatNo. 116004500) and LysingMatrix A tubes (CatNo. 16910050). Protein extracts were obtained using500 μL/tissue of cold T-PER buffer (ThermoFisher, CatNo. 78510) withProtease inhibitors (Sigma-Aldich, CatNo. S8820-20TAB). Soluble proteinfractions were used to measure cytokine levels (IL-4) using ELISA kit(BD Biosciences® #555232). Results were represented as percent ofinhibition relative to unsensitized and sensitized-only treated animalsVehicle for presently disclosed compounds was 60:40 H₂O:EtOH and 1:1Acetone:EtOH for AN2718. (n=5-15 animals per treatment group).

The following results were obtained:

Oxazolone DTH @ 3% w/v Compound Tested Edema % inhibition IL-4 %inhibition A 44 J 10 B 48 C 53 41 R 24 D 53 T 31 53 I 36 E 51 G 41 U 18H 14 V 5 W 22 X 15 Y 0 FK506 32 (@1%) AN2728 (2%)  0 (@2%) 76 (@2%)

Compound C was further analyzed at various dosages against 0.4 mg/ear ofAN278 by the above protocol, data representing the average ±S.E. ofcumulative data from three independent experiments (n=12-15 mice pergroup) is shown below:

Edema (% IL-4 (% MPO (% Compound Tested Dose (Mg/ear) inhibition)inhibition) inhibition) Compound C 0.2 23 ± 4 33 ± 9  22 ± 9  0.6 53 ± 541 ± 10 67 ± 23 1 72 ± 4 62 ± 11 81 ± 5  Compound T 0.2 20 ± 4 30 ± 140.6 31 ± 6 41 ± 18 1 53 ± 8 71 ± 3  Compound E 0.6 22 1 51 ± 9 CompoundG 0.6 41 AN2728 0.4 17 ± 5 76 ± 9  36 ± 12

Example K

P. acnes-Induced Pro-Inflammatory Cytokines on Human NHEKs

Normal human epidermal keratinocytes (NHEKs) from neonatal donors wereobtained from Thermo-Fisher (Cat No. C-001-5C). Cells were cultured in96-well plates for 24 hours with EpiLife media (Cat No. MEPI500CA)supplemented with keratinocytes growth supplement (Cat No. S0015). OnDay 2, media was removed and replaced with supplement-depleted mediumfor 24 hours. On Day 3, media was removed and cells were pre-treatedwith test materials (≤30 μM) for 2 hours and later co-treated with testmaterials and live P. acnes (ATCC® 6919™) at 10⁷ CFU for 24 hours at 37°C. and 5% CO₂. After incubation, cell media supernatants were harvestedand used to measure pro-inflammatory cytokine levels (IL-8) using ELISAkits (BD Biosciences® #555244). Results were represented as percent ofinhibition relative to untreated and P. acnes-only treated cells. IC₅₀values were determined by non-linear regression analysis using thefour-parameter logistic equation.

The following results were obtained:

P. acnes- NHEK Compound IL-8 Protein Tested IC₅₀ (μM) A 0.12 C 0.04 F1.69 E 0.003 G 0.068 H 0.02 V 0.003 Clobetasol 0.033

Example L Phytohemagglutinin (PHA)-Induced Cytokines on PBMCs

Cryopreserved human Peripheral Blood Mononuclear cells (PBMCs) fromhealthy adult donors were obtained from Zen Bio, Inc (Cat No.SER-PBMC-F). Cells were cultured in 96-well plates with lymphocyte media(Cat No. LYMPH-1) and were pre-treated with test materials (≤100 μM) for2 hours and later co-treated with test materials and PHA-L (SigmaAldrich, Cat No. 11249738001) at 20 μg/mL and incubated for 24 hours at37° C. and 5% CO₂. After incubation, cell media supernatants wereharvested and used to measure cytokine levels (IL-2, IFNγ) using ELISAkits (R&D Systems® # DY202, # DY285). Results were represented aspercent of inhibition relative to untreated and PHA-only treated cells.IC₅₀ values were determined by non-linear regression analysis using thefour-parameter logistic equation.

The following results were obtained:

PHA-PBMCs IC₅₀ (μM) Compound Tested IL-2 IFNγ C 0.9 >10 T 0.1 >10 E 4.11.4 G 3.3 >10 AN2728 0.04 0.3 FK506 7 × 10−9 5 × 10−7

Example M Concanavalin-A (ConA)-Induced Cytokines on PBMCs

Cryopreserved human Peripheral Blood Mononuclear cells (PBMCs) fromhealthy adult donors were obtained from Zen Bio, Inc (Cat No.SER-PBMC-F). Cells were cultured in 96-well plates with lymphocyte media(Cat No. LYMPH-1) and were pre-treated with test materials (≤100 μM) for2 hours and later co-treated with test materials and ConA (SigmaAldrich, Cat No. C5275) at 20 μg/mL and incubated for 24 hours at 37° C.and 5% CO₂. After incubation, cell media supernatants were harvested andused to measure cytokine levels (IL-2, IFNγ) using ELISA kits (R&DSystems® # DY202, # DY285). Results were represented as percent ofinhibition relative to untreated and ConA-only treated cells. IC₅₀values were determined by non-linear regression analysis using thefour-parameter logistic equation.

The following results were obtained:

Concanavalin A-PBMCs IC₅₀ (μM) Compound Tested IL-13 IL-17 C 8.2 0.5 T0.1 69.7 E 1.5 11.4 G 0.02 94.2 AN2728 3.8 3.1 FK506 0.6 4 × 10⁻⁷

Example N LPS/IFNγ-Induced Cytokines on CD14+ Monocytes

Cryopreserved human peripheral blood monocytes cells (CD14+) fromhealthy adult donors were obtained from Zen Bio, Inc (Cat No.SER-CD14-F). Cells were cultured in 96-well plates with lymphocyte media(Cat No. LYMPH-1) and were pre-treated with test materials (≤100 μM) for2 hours and later co-treated with test materials and 50 μg/mL LPS, 5μg/mL IFNγ (Sigma Aldrich, Cat No. L4321, SRP3058) and incubated for 24hours at 37° C. and 5% CO₂. After incubation, cell media supernatantswere harvested and used to measure cytokine levels (IL-23) using ELISAkits (R&D Systems® # DY1290). Results were represented as percent ofinhibition relative to untreated and ConA-only treated cells. IC₅₀values were determined by non-linear regression analysis using thefour-parameter logistic equation.

The following results were obtained:

LPS/IFNγ-CD14+ monocytes IC₅₀ (μM) Compound Tested IL-23 C 0.19 T 0.05 E11.15 G 3.08 AN2728 0.65 FK506 7 × 10⁻⁸

Example O Anti-CD3/CD28+IL-4-Induced Cytokines on PBMCs

Cryopreserved human Peripheral Blood Mononuclear cells (PBMCs) fromhealthy adult donors were obtained from Zen Bio, Inc (Cat No.SER-PBMC-F). Cells were cultured in 96-well plates with lymphocyte media(Cat No. LYMPH-1) and were pre-treated with test materials (≤100 μM) for2 hours and later co-treated with test materials and anti-CD3/CD28 beads(Thermo-Fisher; Cat No. 11131D) and 50 ng/mL recombinant human IL-4 (R&DSystems® #204-IL) for 48 hours at 37° C. and 5% CO₂. After incubation,cell media supernatants were harvested and used to measure cytokinelevels (IL-22, IL-31) using ELISA kits (R&D Systems® # DY782, # DY2824).Results were represented as percent of inhibition relative to untreatedand anti-CD3/CD28+IL-4 only treated cells. IC₅₀ values were determinedby non-linear regression analysis using the four-parameter logisticequation.

The following results were obtained:

TCR/IL-4-PBMCs IC₅₀ (μM) Compound Tested IL-22 IL-31 C >25  1 × 10⁻⁸T >25 0.001 E >25 0.001 G >25 <1 × 10⁻⁸ AN2728 2 8.E−06 FK506 7.E−084.E−04

Example P Calcipotriol-Induced TSLP In Vivo

CD1 mice were topically exposed to 4 nmol/ear Calcipotriol. Five minutesafter challenge compounds were applied. Twenty-four hours later, proteinsamples were extracted from ear skin biopsies and analyzed for TSLPlevels by ELISA method. Vehicle for compounds were 60:40 EtOH:H₂O(Compound C) or 1:1 EtOH:Acetone (AN2728). Data represents average ±S.E.of a representative set from 2 independent experiments (n=6 mice pergroup). *p value <0.05; **p value ≤0.01 by Student t test compared toCalcipotriol+vehicle-only treated animals ns equals not significant.

The following results were obtained:

AN2728 Compound C AVG − AVG − TSLP TSLP (pg/6 Dose (pg/6 mm % mm %(μg/ear) biopsy) SEM inhb biopsy) SEM inhb Untreated 435.2 16.8 Calc +3159.4 595.7 4630.7 1236.1 Vehicle 4.0 2753.6 836.6 15 2495.1 802.7 5140.0 1156.1 374.1 74 2235.3 824.3 57 400.0 759.9 148.2 88 352.1 73.5 102

Example Q 8-Week Clinical Study of Compound E (1%), Vehicle and BenzoylPeroxide (3%)

A multi-site use single-blinded study was conducted in healthy male andfemale subjects, aged ≥18 yo with evaluator assessed mild to moderateacne, to evaluate the potential efficacy of test skincare product byutilizing subjective questionnaires, visual evaluations and digitalphotography (≥15 per group). Subjects used the assigned product at homefor 8 weeks. Subjects returned post baseline at week 2, 4 and 8. At eachvisit subjects underwent expert clinical grading and test sitephotography. At Visit 4, subjects also completed a Self-PerceptionQuestionnaire (SPQ). *Values are given as mean±S.E. *p value ≤0.05; **pvalue ≤0.01 by Student t test between group differences from IGA scalevalues from baseline.

The following results were obtained:

Compound Tested (% Investigator Global Assesment (IGA) Scale w/w)Baseline 2 week 4 week 8 week Vehicle (n = 15) 2 3 3 3 E (1%; n = 18) 32 1 0 BPO (3%; n = 15) 3 2 1 1

Facial Cream (1% Compound E) was tested in a randomized single-blindvehicle-controlled study (Active, n=18; Vehicle, n=14) to demonstratethe safety and tolerability in subjects with mild to moderate facialacne. The severity of acne signs and symptoms on the faces of >18 yosubjects were clinically assessed by IGA scale during an 8-week Studyperiod. In addition, UV light mode was utilized to observe porphyrinsfluorescence (orange-red dots). Several subjects using Compound E facialcream demonstrated marked visual improvement in the signs & symptoms ofacne as well as reduction in porphyrins during and after weeks 2-8 ofapplication. Compound E facial cream was well tolerated clinically inhuman subjects with acne prone skin and significantly outperforms BPO onthe acne IGA clinical scale at week 2 and week 8. Moreover, a reductionin porphyrins on the face, is observed suggesting a reduction in P.acnes counts in vivo, supporting in vitro findings.

EQUIVALENTS

Those skilled in the art will recognize, or be able to ascertain usingno more than routine experimentation, that while the invention hereinhas been described with reference to particular embodiments, it is to beunderstood that these embodiments are merely illustrative of theprinciples and applications of the present invention. It is therefore tobe understood that numerous modifications may be made to theillustrative embodiments and that other arrangements may be devisedwithout departing from the spirit and scope of the present invention asdefined by the appended claims.

In the claims, articles such as “a,” “an,” and “the” may mean one ormore than one unless indicated to the contrary or otherwise evident fromthe context. Claims or descriptions that include “or” between one ormore members of a group are considered satisfied if one, more than one,or all of the group members are present in, employed in, or otherwiserelevant to a given product or process unless indicated to the contraryor otherwise evident from the context. The invention includesembodiments in which exactly one member of the group is present in,employed in, or otherwise relevant to a given product or process. Theinvention includes embodiments in which more than one, or all of thegroup members are present in, employed in, or otherwise relevant to agiven product or process. Furthermore, it is to be understood that theinvention encompasses all variations, combinations, and permutations inwhich one or more limitations, elements, clauses, descriptive terms,etc., from one or more of the listed claims is introduced into anotherclaim. For example, any claim that is dependent on another claim can bemodified to include one or more limitations found in any other claimthat is dependent on the same base claim.

Where elements are presented as lists, e.g., in Markush group format, itis to be understood that each subgroup of the elements is alsodisclosed, and any element(s) can be removed from the group. It shouldit be understood that, in general, where the invention, or aspects ofthe invention, is/are referred to as comprising particular elements,features, etc., certain embodiments of the invention or aspects of theinvention consist, or consist essentially of, such elements, features,etc. For purposes of simplicity, those embodiments have not beenspecifically set forth in haec verba herein. It is noted that the term“comprising” is intended to be open and permits the inclusion ofadditional elements or steps.

Where ranges are given, endpoints are included. Furthermore, it is to beunderstood that unless otherwise indicated or otherwise evident from thecontext and understanding of one of ordinary skill in the art, valuesthat are expressed as ranges can assume any specific value or subrangewithin the stated ranges in different embodiments of the invention, tothe tenth of the unit of the lower limit of the range, unless thecontext clearly dictates otherwise.

In addition, it is to be understood that any particular embodiment ofthe present invention that falls within the prior art may be explicitlyexcluded from any one or more of the claims. Since such embodiments aredeemed to be known to one of ordinary skill in the art, they may beexcluded even if the exclusion is not set forth explicitly herein. Anyparticular embodiment of the compositions of the invention (e.g., anytargeting moiety, any disease, disorder, and/or condition, any linkingagent, any method of administration, any therapeutic application, etc.)can be excluded from any one or more claims, for any reason, whether ornot related to the existence of prior art.

Publications discussed above and throughout the text are provided solelyfor their disclosure prior to the filing date of the presentapplication. Nothing herein is to be construed as an admission that theinventors are not entitled to antedate such disclosure by virtue ofprior disclosure.

1. A compound represented by the formula:

or a pharmaceutically acceptable salt, solvate, prodrug or esterthereof; wherein: X is —C(O)—, or a covalent bond; Y is hydroxyl, —NH₂,—O—C₁-C₅ alkyl or C₁-C₅ alkyl; A and B are independently selected fromNR, N(C₁-C₅ alkyl), N(C₁-C₅ alkylene-R), N(C₁-C₅ alkylene)-CN, N(C₁-C₅alkylene carboxyl), each of said alkyl or alkylene group optionallysubstituted with one or more R groups, —O—, a R-substituted orunsubstituted C₁-C₅ alkylene, a R-substituted or unsubstituted O—C₁-C₅alkylene, a R-substituted or unsubstituted arylene or a R-substituted orunsubstituted heteroarylene having 1-4 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur, or a R-substituted orunsubstituted C₃-C₆ cycloalkylene or R-substituted or unsubstitutedC₃-C₆ heterocycloalkylene having 1-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur; or A and B together form aR-substituted or unsubstituted arylene or a R-substituted orunsubstituted heteroarylene having 1-4 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur, or a R-substituted orunsubstituted C₃-C₆ cycloalkylene or R-substituted or unsubstitutedC₃-C₆ heterocycloalkylene having 1-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur; D is —OH or —O(C₁-C₅ alkyl), E and E′are independently selected from H, and C₁-C₅ alkyl; and R is,independently, H, C₁-C₅ alkyl, OH, S(C₁-C₅ alkyl), NH(C₁-C₅ alkyl),NH(C₁-C₅ alkylene carboxyl), NH(C₁-C₅ alkylene guanidine), N(C₁-C₅alkylene amidine), N(C₁-C₅ alkylene amide), CF₃, —CN, —COOH, or O(C₁-C₅alkyl); provided that when A and B are both —CH₂—, D is hydroxyl, X is—C(O)—, and E is hydrogen, Y cannot be hydroxyl, —OCH₃ or —CH₃.
 2. Thecompound of claim 1, wherein Y is selected from OH and —NH₂.
 3. Thecompound of claim 1 wherein A is selected from —CH₂—, —CH₂NH—, N-methyl,—O— and N(C₁-C₅ alkylene carboxyl).
 4. The compound of claim 1 wherein Bis selected from —O— and unsubstituted O—C₁-C₅ alkylene.
 5. The compoundof claim 1 wherein B is —CH₂—.
 6. The compound of claim 1 wherein A andB together form a R-substituted or unsubstituted arylene or aR-substituted or unsubstituted heteroarylene having 1-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or aR-substituted or unsubstituted C₃-C₆ cycloalkylene or R-substituted orunsubstituted C₃-C₆ heterocycloalkylene having 1-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur.
 7. The compoundof claim 1 wherein A and B together form an unsubstituted C₃-C₆heterocycloalkylene having 1-4 nitrogen atoms or an unsubstitutedheteroarylene having 1-4 nitrogen atoms.
 8. The compound of claim 1wherein E and E′ are each methyl.
 9. The compound of claim 1 wherein Dis —OH.
 10. The compound of claim 1, wherein the compound is representedby the formula:

or a pharmaceutically acceptable salt, solvate, prodrug or esterthereof; wherein: Y is hydroxyl, —NH₂, —O—C₁-C₅ alkyl or C₁-C₅ alkyl; Aand B are independently selected from NR, N(C₁-C₅ alkyl), N(C₁-C₅alkylene)-R, N(C₁-C₅ alkylene)-CN, N(C₁-C₅ alkylene carboxyl), each ofsaid alkyl or alkylene group optionally substituted with one or more Rgroups, —O—, a R-substituted or unsubstituted C₁-C₅ alkylene, aR-substituted or unsubstituted O—C₁-C₅ alkylene, a R-substituted orunsubstituted arylene or a R-substituted or unsubstituted heteroarylenehaving 1-4 heteroatoms independently selected from nitrogen, oxygen, orsulfur, or a R-substituted or unsubstituted C₃-C₆ cycloalkylene orR-substituted or unsubstituted C₃-C₆ heterocycloalkylene having 1-4heteroatoms independently selected from nitrogen, oxygen, or sulfur; orA and B together form a R-substituted or unsubstituted arylene or aR-substituted or unsubstituted heteroarylene having 1-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or aR-substituted or unsubstituted C₃-C₆ cycloalkylene or R-substituted orunsubstituted C₃-C₆ heterocycloalkylene having 1-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur; R is,independently, —H, C₁-C₅ alkyl, OH, S(C₁-C₅ alkyl), NH(C₁-C₅ alkyl),NH(C₁-C₅ alkylene carboxyl), NH(C₁-C₅ alkylene guanidine), N(C₁-C₅alkylene amidine), N(C₁-C₅ alkylene amide) or O(C₁-C₅ alkyl); providedthat when A and B are both —CH₂—, Y cannot be hydroxyl, —OCH₃ or —CH₃.11-13. (canceled)
 14. The compound of claim 1, wherein the compound isrepresented by the formula:

or a pharmaceutically acceptable salt, solvate, prodrug or esterthereof; wherein: Y is hydroxyl, —NH₂, —O—C₁-C₅ alkyl, or C₁-C₅ alkyl; Aand B together form a R-substituted or unsubstituted arylene or aR-substituted or unsubstituted heteroarylene having 1-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or aR-substituted or unsubstituted C₃-C₆ cycloalkylene or R-substituted orunsubstituted C₃-C₆ heterocycloalkylene having 1-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur; D is —OH,—O(C₁-C₅ alkyl), E and E′ are independently selected from —H and C₁-C₅alkyl; and R is, independently, H, C₁-C₅ alkyl, OH, S(C₁-C₅ alkyl),NH(C₁-C₅ alkyl), NH(C₁-C₅ alkylene carboxyl), NH(C₁-C₅ alkyleneguanidine), N(C₁-C₅ alkylene amidine), N(C₁-C₅ alkylene amide), CF₃,—CN, —COOH, or O(C₁-C₅ alkyl); provided that when A and B are both—CH₂—, D is hydroxyl, and E is hydrogen, Y cannot be hydroxyl, —OCH₃ or—CH₃. 15-17. (canceled)
 18. The compound of claim 1, wherein thecompound is represented by the formula:

or a pharmaceutically acceptable salt, solvate, prodrug or esterthereof; wherein: Y is hydroxyl, —NH₂, —O—C₁-C₅ alkyl or C₁-C₅ alkyl; Ais selected from R, C₁-C₅ alkyl, (C₁-C₅ alkylene)-R, (C₁-C₅alkylene)-CN, (C₁-C₅ alkylene)-carboxyl, each of said alkyl or alkylenegroup optionally substituted with one or more R groups; B is anunsubstituted C₁-C₂ alkylene; or A, B and the nitrogen atom bound to Aand B form a R-substituted or unsubstituted C₃-C₆ heterocycloalkylenehaving 1-4 heteroatoms independently selected from nitrogen, oxygen, orsulfur; and R is, independently, —H, C₁-C₅ alkyl, OH, S(C₁-C₅ alkyl),NH(C₁-C₅ alkyl), NH(C₁-C₅ alkylene carboxyl), NH(C₁-C₅ alkyleneguanidine), N(C₁-C₅ alkylene amidine), N(C₁-C₅ alkylene amide), CF₃,—CN, —COOH, or O(C₁-C₅ alkyl).
 19. The compound of claim 1, wherein thecompound is represented by the formula:

or a pharmaceutically acceptable salt, solvate, prodrug or esterthereof; wherein: Y is hydroxyl, —NH₂, —O—C₁-C₅ alkyl or C₁-C₅ alkyl; Ais an unsubstituted C₁-C₂ alkylene; B is selected from R, C₁-C₅ alkyl,(C₁-C₅ alkylene)-R, (C₁-C₅ alkylene)-CN, (C₁-C₅ alkylene)-carboxyl, eachof said alkyl or alkylene group optionally substituted with one or moreR groups; or A, B and the nitrogen atom bound to A and B form aR-substituted or unsubstituted C₃-C₆ heterocycloalkylene having 1-4heteroatoms independently selected from nitrogen, oxygen, or sulfur; andR is, independently, —H, C₁-C₅ alkyl, OH, S(C₁-C₅ alkyl), NH(C₁-C₅alkyl), NH(C₁-C₅ alkylene carboxyl), NH(C₁-C₅ alkylene guanidine),N(C₁-C₅ alkylene amidine), N(C₁-C₅ alkylene amide), CF₃, —CN, —COOH, orO(C₁-C₅ alkyl).
 20. A compound of claim 1, wherein the compound isrepresented by the formula:

or a pharmaceutically acceptable salt, solvate, prodrug or esterthereof; wherein: Y is hydroxyl, —NH₂, —O—C₁-C₅ alkyl or C₁-C₅ alkyl; Ais NH, N(C₁-C₅ alkyl), N(C₁-C₅ alkylene carboxyl), or a R-substituted orunsubstituted C₁-C₅ alkylene; B is NH, N(C₁-C₅ alkyl), N(C₁-C₅ alkylenecarboxyl), or a R-substituted or unsubstituted C₁-C₅ alkylene; or A andB together form a R-substituted or unsubstituted arylene or aR-substituted or unsubstituted heteroarylene having 1-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or aR-substituted or unsubstituted C₃-C₆ cycloalkylene or R-substituted orunsubstituted C₃-C₆ heterocycloalkylene having 1-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur; R is,independently, C₁-C₅ alkyl, OH, S(C₁-C₅ alkyl), NH(C₁-C₅ alkyl),NH(C₁-C₅ alkylene carboxyl), NH(C₁-C₅ alkylene guanidine), N(C₁-C₅alkylene amidine), N(C₁-C₅ alkylene amide) or O(C₁-C₅ alkyl); providedthat when A and B are both —CH₂—, Y cannot be hydroxyl, —OCH₃ or —CH₃.21-29. (canceled)
 30. The compound of claim 20, wherein(2S)-1-{[(1R)-1-carboxy-2-{[(2E)-3,7,11,15-tetramethylhexadec-2-en-1-yl]sulfanyl}ethyl]carbamoyl}pyrrolidine-2-carboxylicacid and (2R)-2-{[bis(carboxymethyl)carbamoyl]amino}-3-{[(2E)-3,7,11,15-tetramethylhexadec-2-en-1-yl]sulfanyl}propanoicacid are excluded.
 31. A compound of claim 1, wherein the compound isrepresented by the formula:

or a pharmaceutically acceptable salt, solvate, prodrug or esterthereof; wherein: Y is hydroxyl, —NH₂, —O—C₁-C₅ alkyl or C₁-C₅ alkyl; Ais hydrogen, an unsubstituted C₁-C₂ alkyl or CH₂COOH; B is anunsubstituted C₁-C₂ alkylene; or A, B and the nitrogen atom bound to Aand B form a R-substituted or unsubstituted C₃-C₆ heterocycloalkylenehaving 1-4 heteroatoms independently selected from nitrogen, oxygen, orsulfur; and R is C₁-C₅ alkyl, OH, S(C₁-C₅ alkyl), NH(C₁-C₅ alkyl),NH(C₁-C₅ alkylene carboxyl), NH(C₁-C₅ alkylene guanidine), N(C₁-C₅alkylene amidine), N(C₁-C₅ alkylene amide), or O(C₁-C₅ alkyl). 32-36.(canceled)
 37. The compound of claim 31, wherein(2S)-1-{[(1R)-1-carboxy-2-{[(2E)-3,7,11,15-tetramethylhexadec-2-en-1-yl]sulfanyl}ethyl]carbamoyl}pyrrolidine-2-carboxylicacid and(2R)-2-{[bis(carboxymethyl)carbamoyl]amino}-3-{[(2E)-3,7,11,15-tetramethylhexadec-2-en-1-yl]sulfanyl}propanoicacid are excluded.
 38. A compound of claim 1, wherein the compound isrepresented by the formula:

or a pharmaceutically acceptable salt, solvate, prodrug or esterthereof; wherein: Y is hydroxyl, —NH₂, —O—C₁-C₅ alkyl or C₁-C₅ alkyl; Ais an unsubstituted C₁-C₂ alkylene; B is hydrogen, an unsubstitutedC₁-C₂ alkyl or CH₂COOH; or A, B and the nitrogen atom bound to A and Bform a R-substituted or unsubstituted C₃-C₆ heterocycloalkylene having1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;and R is C₁-C₅ alkyl, OH, S(C₁-C₅ alkyl), NH(C₁-C₅ alkyl), NH(C₁-C₅alkylene carboxyl), NH(C₁-C₅ alkylene guanidine), N(C₁-C₅ alkyleneamidine), N(C₁-C₅ alkylene amide), or O(C₁-C₅ alkyl). 39-42. (canceled)43. The compound of claim 38, wherein(2S)-1-{[(1R)-1-carboxy-2-{[(2E)-3,7,11,15-tetramethylhexadec-2-en-1-yl]sulfanyl}ethyl]carbamoyl}pyrrolidine-2-carboxylicacid and(2R)-2-{[bis(carboxymethyl)carbamoyl]amino}-3-{[(2E)-3,7,11,15-tetramethylhexadec-2-en-1-yl]sulfanyl}propanoicacid are excluded.
 44. A compound selected from the group consisting of:

or a pharmaceutically acceptable salt, solvate, prodrug or ester of anyof the above compounds.
 45. The compound of claim 44, wherein thecompound is

or a pharmaceutically acceptable salt, solvate, prodrug or esterthereof.
 46. The compound of claim 44, wherein the compound is

or a pharmaceutically acceptable salt, solvate, prodrug or esterthereof.
 47. The compound of claim 44, wherein the compound is

or a pharmaceutically acceptable salt, solvate, prodrug or esterthereof.
 48. The compound of claim 44, wherein the compound is

or a pharmaceutically acceptable salt, solvate, prodrug or esterthereof.
 49. A compound selected from the group consisting of:

or a pharmaceutically acceptable salt, solvate, prodrug or ester of anyof the above compounds.
 50. (canceled)
 51. A pharmaceutical compositionsuitable for administration by a human comprising an effective amount ofa compound according to claim 1 and one or more of a pharmaceuticallyacceptable adjuvant, a pharmaceutically acceptable carrier and apharmaceutically acceptable vehicle.
 52. A cosmeceutical compositionsuitable for administration to a human comprising an effective amount ofa compound according to claim 1 and one or more of a pharmaceuticallyacceptable adjuvant, a comseceutically acceptable carrier and apharmaceutically acceptable vehicle.
 53. A method for treating orameliorating inflammation in a subject in need thereof, comprising thestep of administering to the subject an effective amount of a compoundaccording to claim
 1. 54. (canceled)
 55. The method according to claim53, wherein the inflammation is associated with a condition, disease ordisorder selected from a spinal cord injury, asthma, an autoimmunedisease, chronic obstructive pulmonary disease, inflammatory responsesof the immune system, a skin disease, irritable bowel syndrome, and aneurodegenerative disorder. 56-62. (canceled)
 63. The method of claim55, wherein the neurodegenerative disorder is selected from Parkinson'sdisease, Alzheimer's disease, Huntington's disease, dementiapugilistica, Pick's disease, Guam parkinsonism dementia complex,fronto-temporal dementia, corticobasal degeneration,pallido-pontal-nigral degeneration, progressive supranuclear palsy,dementia with Lewy bodies (DLB) and multiple system atrophy (MSA).64-68. (canceled)